Inhibitors of histone deacetylase

ABSTRACT

Disclosed are compounds which inhibit histone deacetylase (HDAC) enzymatic activity. Also disclosed are pharmaceutical compositions comprising such compounds as well as methods to treat conditions, particularly proliferative conditions, mediated at least in part by HDAC.

CROSS-REFERENCE TO RELATED CASES

This application claims the benefit under 35 U.S.C. §119(e) of U.S.Provisional Application Ser. No. 60/559,692 flied Apr. 1, 2004, which isincorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to compounds which inhibit histone deacetylase(HDAC) enzymatic activity. This invention is also directed topharmaceutical compositions comprising such compounds as well as totreat conditions, particularly proliferative conditions, mediated atleast in part by HDAC.

REFERENCES

The following publications, patents and patent applications are cited inthis application as superscript numbers:

-   1 Marks, et al., Nature Reviews: Cancer 1: 194-202 (2001)-   2 Finnin, et al., Nature, 401:188-193 (1999)-   3 Geerts, et al., European Patent Application Publication No. 0 827    742, published Mar. 11, 1998

All of the above publications, patents and patent applications areherein incorporated by reference in their entirety to the same extent asif each individual publication, patent or patent application wasspecifically and individually indicated to be incorporated by referencein its entirety.

2. State of the Art

In all eukaryotic cells, genomic DNA in chromatine associates withhistones to form nucleosomes. Each nucleosome consists of a proteinoctamer made up of two copies of each histone: H2A, H2B, H3 and H4. DNAwinds around this protein core, with the basic amino acids of thehistones interacting with the negatively charged phosphate groups of theDNA. The most common posttranslational modification of these corehistones is the reversible acetylation of the ε-amino groups ofconserved highly basic N-terminal lysine residues. The steady state ofhistone acetylation is established by the dynamic equilibrium betweencompeting histone acetyltransferase(s) and histone deacetylase(s) hereinreferred to as HDAC. Histone acetylation and deacetylation has long beenlinked to transcriptional control. The recent cloning of the genesencoding different histone acetyltransferases and histone deacetylasesprovide a possible explanation for the relationship between histoneacetylation and transcriptional control. The reversible acetylation ofhistones can result in chromatin remodeling and as such act as a controlmechanism for gene transcription. In general, hyperacetylation ofhistones facilitates gene expression, whereas histone deacetylation iscorrelated with transcriptional repression. Histone acetyltransferaseswere shown to act as transcriptional coactivators, whereas deacetylaseswere found to belong to transcriptional repression pathways.

The dynamic equilibrium between histone acetylation and deacetylation isessential for normal cell growth. Inhibition of histone deacetylationresults in cell cycle arrest, cellular differentiation, apoptosis andreversal of the transformed phenotype. Therefore, HDAC inhibitors canhave great therapeutic potential in the treatment of cell proliferativediseases or conditions.¹

The study of inhibitors of histone deacetylases (HDAC) indicates thatindeed these enzymes play an important role in cell proliferation anddifferentiation. The inhibitor Trichostatin A (TSA) causes cell cyclearrest at both the G1 and G2 phases, reverts the transformed phenotypeof different cell lines, and induces differentiation of Friend leukemiacells and others. TSA (and suberoylanilide hydroxamic acid SAHA) havebeen reported to inhibit cell growth, induce terminal differentiation,and prevent formation of tumors in mice.²

Trichostatin A has also been reported to be useful in the treatment offibrosis, e.g., liver fibrosis and liver chirrhosis.³

In view of the above, there is an ongoing need forinhibitors/antagonists of HDAC.

SUMMARY OF THE INVENTION

This invention provides compounds which inhibit HDAC activity and,accordingly, are useful as anti-proliferative agents in the treatment ofproliferative diseases.

Accordingly, in one of its composition aspects, this invention isdirected to a compound of Formula I:

wherein:

R is selected from the group consisting of hydrogen, aryl, substitutedaryl, heteroaryl substituted heteroaryl, alkyl and substituted alkyl;

R¹² is selected from the group consisting of —NR¹⁴OH, —OH, —NR¹⁴R¹⁵,—OR¹⁴, —(C₁-C₆)alkylene-SR¹⁴, —(C₁-C₆)alkylene-OR¹⁴,—(C₁-C₆)alkylene-NR¹⁴R¹⁵, —CF₃;

where R¹⁴ and R¹⁵ are independently selected from the group consistingof hydrogen, (C₁-C₆)alkyl, (C₁-C₆)substituted alkyl, aryl, substitutedaryl and where R¹⁴ and R¹⁵ together with the nitrogen atom bound theretoform a heterocyclic or substituted heterocyclic ring;

V, W, X, Y, and Z form a 5-membered heteroaryl where W, X, and Y areindependently selected from ═C(R¹¹)—, —N═, —N(R¹⁴)—, —O—, —S—, —S(O)—,and/or —S(O)₂—, and V and Z independently form ═C(R¹⁴)— and/or >N— whereR¹⁴ is as defined above and provided that at least one of V, W, X, Y andZ is ═C(R¹⁴)—, and further provided that the ring formed by V, W, X, Y,and Z is not a thiophene;

the ring defined by A above is selected from the group consisting ofcycloakylene, substituted cycloalkylene, heterocyclene, substitutedheterocyclene, arylene, heteroarylene, -het-(L²)_(b)-het-,-het-(L²)_(b)-cyclo-, -cyclo-(L²)_(b)-het-, and -cyclo-(L²)_(b)-cyclo-;

where each b is independently 0 or 1;

L² is selected from the group consisting of a covalent bond,(C₁-C₄)alkylene, substituted (C₁-C₄)alkylene, —NH(C₁-C₄)alkylene,(C₁-C₄)alkyleneNH—, provided that the nitrogen atom of the—NH(C₁-C₄)alkylene and (C₁-C₄)alkyleneNH— group are not attached to anitrogen atom in the het or in cyclo groups;

T is selected from the group consisting of a bond,—SO₂—[(C₁-C₃)alkylene]_(p)-, —[(C₁-C₃)alkylene], —SO₂—,—NR¹⁶SO₂—[(C₁-C₃)alkylene]_(p)-, —SO₂NR¹⁶—[(C₁-C₃)alkylene]_(p)-,—C(O)—[(C₁-C₃)alkylene]_(p)-, —[(C₁-C₃)alkylene]_(p)-C(O)—,—NR¹⁶C(O)—[(C₁-C₃)alkylene]_(p)—, —C(O)NR¹⁶—[(C₁-C₃)alkylene]_(p)-,—N(R¹⁶)—[(C₁-C₃)alkylene]_(p) and (C₁-C₃)alkylene where p is zero or oneand R¹⁶ is hydrogen, alkyl, aryl, or heteroaryl, provided that when T isconnected to A at a nitrogen atom and T is—SO₂NR¹⁶—[(C₁-C₃)alkylene]_(p)-, —C(O)NR¹⁶—[(C₁-C₃)alkylene]_(p)-, or—N(R¹⁶)—[(C₁-C₃)alkylene]_(p) then p is not zero;

Q is selected from the group consisting of a covalent bond, —O—,(C₁-C₃)alkylene, —C(O)—, —SO₂—, —NR¹C(O)NR¹—, —NR¹C(O)—, —C(O)NR¹—,—(C₁-C₃-alkylene)_(p)NR¹— and —NR¹—(C₁-C₃-alkylene)_(p) where R¹ ishydrogen or alkyl and p is zero or one, provided that when Q is one of—NR¹C(O)NR¹—, —NR¹C(O)—, —C(O)NR¹—, —(C₁-C₃-alkylene)_(p)NR¹—, or—NR¹—(C₁-C₃-alkylene)_(p) and p is not zero Q is not attached to anitrogen atom;

L is selected from the group consisting of a covalent bond,(C₁-C₄)alkylene, substituted (C₁-C₄)alkylene, (C₂-C₄)alkenylene, andsubstituted (C₂-C₄)alkenylene, (C₃-C₈)cycloalkylene, and substituted(C₃-C₈)cycloalkylene;

and tautomers, isomers, prodrugs and pharmaceutically acceptable saltsthereof.

Preferred heteroaryl groups defined by V, W, X, Y and Z include furan,imidazole, pyrrazole, isoxazole, isothiazole, oxadiazole, thiazole,tetrazole, triazole, oxazole, pyrrole, thiadiazole, and the like,excluding thiophene.

In another of its composition aspects, this invention is directed to acompound of Formula Ia:

wherein:

R is selected from the group consisting of alkyl, substituted alkyl,aryl, substituted aryl, heteroaryl and substituted heteroaryl;

R¹² is selected from the group consisting of —NR¹⁴OH, —OH, —NR¹⁴R¹⁵,—OR¹⁴, —(C₁-C₆)alkylene-SR¹⁴, —(C₁-C₆)alkylene-OR¹⁴,—(C₁-C₆)alkylene-NR¹⁴R¹⁵, —CF₃;

where R¹⁴, R¹⁵ are independently selected from the group consisting ofhydrogen, (C₁-C₆)alkyl, (C₁-C₆)substituted alkyl, aryl, substituted aryland where R¹⁴ and R¹⁵ together with the nitrogen atom bound thereto forma heterocyclic or substituted heterocyclic ring;

the ring defined by A above is selected from the group consisting ofcycloakylene, substituted cycloalkylene, hetrocyclene, substitutedheterocyclene, arylene, heteroarylene, -het-(L²)_(b)-het-,-het-(L²)_(b)-cyclo-, -cyclo-(L²)_(b)-het-, and cyclo-(L²)_(b)-cyclo-;

where each b is independently 0 or 1;

L² is selected from the group consisting of a covalent bond,(C₁-C₄)alkylene, substituted (C₁-C₄)alkylene, —NH(C₁-C₄)alkylene,(C₁-C₄)alkyleneNH—, provided that the nitrogen atom of the—NH(C₁-C₄)alkylene and (C₁-C₄)alkyleneNH— group are not attached to anitrogen atom in the het or in cyclo groups;

T is selected from the group consisting of —SO₂—[(C₁-C₃)alkylene]_(p)-,—[(C₁-C₃)alkylene]_(p)-SO₂—, —NR¹⁶SO₂—[(C₁-C₃)alkylene]_(p)-,—SO₂NR¹⁶—[(C₁-C₃)alkylene]_(p)-, —C(O)—[(C₁-C₃)alkylene]_(p)-,—[(C₁-C₃)alkylene]_(p)-C(O)—, —NR¹⁶C(O)—[(C₁-C₃)alkylene]_(p)-,—C(O)NR¹⁶—[(C₁-C₃)alkylene]_(p)-, —N(R¹⁶)—[(C₁-C₃)alkylene]_(p) and(C₁-C₃)alkylene where p is zero or one and R¹⁶ is hydrogen, alkyl, aryl,or heteroaryl, provided that when T is connected to A at a nitrogen atomand T is —SO₂NR¹⁶—[(C₁-C₃)alkylene]_(p)-,—C(O)NR¹⁶—[(C₁-C₃)alkylene]_(p)—, or —N(R¹⁶)—[(C₁-C₃)alkylene]_(p) thenp is not zero;

W is selected from the group consisting of —O—, —S—, —S(O)—, —S(O)₂— and—NR¹— where R¹ is as defined below;

X and Y is selected from the group consisting of >CH and >N such thatthe 5 membered ring defined by W, X, Y and the two >CH groups is aheteroaryl ring, with the proviso that the ring is not thiophene;

Q is selected from the group consisting of a covalent bond, —O—,(C₁-C₃)alkylene, —C(O)—, —SO₂—, —NR¹C(O)NR¹—, —NR¹C(O)—, —C(O)NR¹—,—(C₁-C₃-alkylene)_(p)NR¹— and —NR¹—(C₁-C₃-alkylene)_(p) where R¹ ishydrogen or alkyl and p is zero or one; provided that Q is not attachedto X, Y or W when W is —O—, —S—, —S(O)—, —S(O)₂— and further providedthat when Q is —NR¹— then Q is attached to a carbon atom of the ringdefined by A above;

L is selected from the group consisting of a covalent bond,(C₁-C₄)alkylene, substituted (C₁-C₄)alkylene, (C₂-C₄)alkenylene, andsubstituted (C₂-C₄)alkenylene, (C₃-C₈)cycloalkylene, and substituted(C₃-C₈)cycloalkylene;

and tautomers, isomers, prodrugs and pharmaceutically acceptable saltsthereof.

Preferred A rings in Formulae I and Ia include by are not limited tooptionally substituted piperidine, piperazine, morpholine, piperazinone,piperazindione, azetidine, hydantoin, oxazolidine,octahydro-pyrrolo[3,4-c]pyrrole, tetrahydropyridine, hexene,pyrrolidine, and the like.

More preferably, when A is a heterocyclic group, the R-T-A-Q fragment ofFormulae I and Ia above is selected from the following structures,wherein b is 0 or 1, each R, R¹ and R¹⁶ are as defined herein above, andfurther wherein each depicted A ring is optionally substituted with from1 to 3 substituents selected from hydrogen, (C₁-C₆)alkyl,(C₁-C₆)substituted alkyl, aryl, and substituted aryl.

Additional preferred A rings include by are not limited to optionallysubstituted bicyclic or spirocyclic groups.

More preferably, when the A moiety is a bicyclic or spirocyclic group,the R-T-A-Q fragment of Formulae I and Ia above is selected from thefollowing structures, wherein b is 0 or 1, each R and R¹⁶ are as definedherein above, and further wherein each depicted A ring is optionallysubstituted with from 1 to 3 substituents selected from hydrogen,(C₁-C₆)alkyl, (C₁-C₆)substituted alkyl, aryl, and substituted aryl.

Preferred A rings also include aromatic rings, including, but notlimited to, optionally substituted phenyl, pyridine, pyridazine,pyrimidine, triazine, and the like. More preferably, when A is anaromatic ring, the R-T-A-Q fragment of Formulae I and Ia above isselected from the following structures, wherein R and T are as definedhereinabove, and further wherein each depicted A ring is optionallysubstituted with from 1 to 3 substituents selected from hydrogen,(C₁-C₆)alkyl, (C₁-C₆)substituted alkyl, aryl, and substituted aryl.

In one preferred embodiment, the compounds of this invention arerepresented by formula II:

where L, R, T, X and Y are as defined above; each R³ is independentlyselected from the group consisting of alkyl, substituted alkyl, aryl,substituted aryl, heteroaryl and substituted heteroaryl; n, z, and z′are independently integers equal to zero, one or two, with the provisothat both z and z′ are not zero;

as well as tautomers, isomers, prodrugs, and pharmaceutically acceptablesalts thereof.

In another preferred embodiment, the compounds of this invention arerepresented by formula III:

where n, z, L, R, R³, T, X and Y are as defined above; as well astautomers, isomers, prodrugs and pharmaceutically acceptable saltsthereof.

In still another preferred embodiment, the compounds of this inventionare represented by formula IV:

where n, z, L, Q, R, R³, T, X and Y are as defined above, z is zero orone,

as well as tautomers, isomers, prodrugs, and pharmaceutically acceptablesalts thereof.

In still another preferred embodiment, the compounds of this inventionare represented by formula V:

where n, z, L, Q, R, R³, T, X and Y are as defined above as well astautomers, isomers, prodrugs, and pharmaceutically acceptable saltsthereof.

In one embodiment, R is preferably aryl and more preferably is phenyl ornaphthyl (e.g., 2-napthyl).

In another embodiment, R is preferably substituted aryl and morepreferably, 3,4-dimethoxyphenyl, 4-trifluoromethoxyphenyl,4-methylphenyl. 4-trifluororomethylphenyl, 4-nitrophenyl,4-acetylphenyl, thiophen-2-yl, biphenyl,5-(N,N-dimethylamino)-naphthalenyl, and 4-fluorophenyl.

In yet another embodiment, R is preferably alkyl or substituted alkyl,more preferably methyl, benzyl, 2-hydroxyethyl, 2-aminoethyl, and2-phenylethyl.

In one embodiment, R³ is alkyl and n is one. In another embodiment, n iszero.

Q is preferably a covalent bond, —NR¹—, —(CH₂)NR¹—, —SO₂—, —C(O)—, or—O—.

In one embodiment, Q is a covalent bond and the ring defined by A aboveis piperidinyl. In still another embodiment, Q is a covalent bond andthe ring defined by A above is piperazinyl.

X is preferably nitrogen and Y is preferably CH.

T is preferably selected from the group consisting of a bond, —SO₂—,—SO₂NH—, —CH₂NR¹⁶—.

In one embodiment, L is a covalent bond. In another embodiment, L is analkenylene group which is preferably ethenylene and more preferablytrans (or Z) ethenylene. In still another embodiment, L is acycloalkylene group, and more preferably cyclopropylene includingcis-cyclopropylene and trans-cyclopropylene. In this application,cis-cyclopropylene (as well as cis-cycloalkylene) refers to the groups:

whereas trans-cyclopropylene (as well as trans-cycloalkylene) refers tothe groups:

Still another class of compounds of this invention includes compounds offormula VI:

where:

R is selected from the group consisting of alkyl, substituted alkyl,aryl, substituted aryl, heteroaryl and substituted heteroaryl;

the ring defined by A above is selected from the group consisting ofcycloalkylene, substituted cycloalkylene, heterocyclene and substitutedheterocyclene;

T is selected from the group consisting of —SO₂—[(C₁-C₃)alkylene]_(p)—,—[(C₁-C₃)alkylene]_(p)-SO₂—, —NR¹⁶SO₂—[(C₁-C₃)alkylene]_(p)-,—SO₂NR¹⁶—[(C₁-C₃)alkylene]_(p)-, —C(O)—[(C₁-C₃)alkylene]_(p)—,—[(C₁-C₃)alkylene]_(p)—C(O)—, —NR¹⁶C(O)—[(C₁-C₃)alkylene]_(p)—,—C(O)NR¹⁶—[(C₁-C₃)alkylene]_(p)—, —N(R¹⁶)—[(C₁-C₃)alkylene]_(p) and(C₁-C₃)alkylene where p is zero or one and R¹⁶ is hydrogen, alkyl, aryl,or heteroaryl, provided that when T is connected to A at a nitrogen atomand T is —SO₂NR¹⁶—[(C₁-C₃)alkylene]_(p)-,—C(O)NR¹⁶—[(C₁-C₃)alkylene]_(p)-, or —N(R¹⁶)—[(C₁-C₃)alkylene]_(p) thenp is not zero;

W is selected from the group consisting of —O—, —S—, —S(O)—, —S(O)₂— and—NR¹— where R¹ is as defined above;

X is selected from the group consisting of >CH and >N such that the 5membered ring defined by W, X and the pendant >CH groups is a heteroarylring;

Q is selected from the group consisting of a covalent bond, —O—,(C₁-C₃)alkylene, —C(O)—, —SO₂—, —NR¹C(O)NR¹—, —NR¹C(O)—, —C(O)NR¹—,—(C₁-C₃-alkylene)_(p)NR¹— and —NR¹—(C₁-C₃-alkylene)_(p) where R¹ ishydrogen or alkyl and p is zero or one, provided that Q is not attachedto X or W when W is —O—, —S—, —S(O)—, —S(O)₂— and further provided thatwhen Q is —NR¹— then Q is attached to a carbon atom of the ring definedby A above;

L is selected from the group consisting of a covalent bond, alkylene,substituted alkylene, alkenylene, substituted alkenylene, cycloalkylene,and substituted cycloalkylene provided that L is attached to a carbonatom of the 5 membered heteroaryl group;

the cyclic structure defined by B, together with the unsaturation in theheteroaryl ring, is selected from the group consisting of cycloalkenyl,substituted cycloalkenyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, unsaturated heterocyclc and substitutedunsaturated heterocyclic; and

and tautomers, isomers, prodrugs, and pharmaceutically acceptable saltsthereof.

Particularly preferred compounds of formula VI include those of formulaVII:

where n, z, K, R³, L, Q, T, and X are as defined above as well astautomers, isomers, prodrugs, and pharmaceutically acceptable saltsthereof.

In one of its pharmaceutical composition aspect, this invention isdirected to a pharmaceutical composition comprising an effective amountof a compound according to any of formulas I-VII and a pharmaceuticallyinert carrier.

In another of its pharmaceutical aspects, this invention is directed topharmaceutical compositions comprising an effective amount of a compoundaccording to any of formulas I-VII, an effective amount of at least oneanti-cancer agent, and a pharmaceutically inert carrier.

In one of its method aspects, this invention is directed to a method forinhibiting a proliferative disorder in a mammalian patient which methodcomprises administering to said patient a pharmaceutical compositioncomprising a pharmaceutically acceptable carrier and a therapeuticallyeffective amount of a compound of formula I-VII or a mixture thereof.

In another of its method aspects, this invention is directed to a methodfor inhibiting a proliferative disorder in a mammalian patient whichmethod comprises administering to said patient a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier, aneffective amount of at least one anti-cancer agent, and atherapeutically effective amount of a compound of formula I-VII or amixture thereof.

In yet another of its method aspects, this invention is directed to amethod for inhibiting a proliferative disorder in a mammalian patientwhich method comprises administering to said patient a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound of formula I-VII or amixture thereof in combination with at least one anti-cancer agent.

For the treatment of the above conditions, the compounds of theinvention may be advantageously employed in combination with one or moreother medicinal agents, more particularly, with other anti-canceragents. Examples of anti-cancer agents are: platinum coordinationcompounds for example cisplatin, carboplatin or oxalyplatin; taxanecompounds for example paclitaxel or docetaxel; topoisomerase Iinhibitors such as camptothecin compounds for example irinotecan ortopotecan; topoisomerase II inhibitors such as anti-tumourpodophyllotoxin derivatives for example etoposide or teniposide;anti-tumour vinca alkaloids for example vinblastine, vincristine orvinorelbine; anti-tumor nucleoside derivatives for example5-fluorouracil, gemcitabine or capecitabine; alkylating agents such asnitrogen mustard or nitrosourea for example cyclophosphamide,chlorambucil, carmustine or lomustine; anti-tumour anthracyclinederivatives for example daunorubicin, doxorubicin, idarubicin ormitoxantrone; BIER antibodies for example trastuzumab; estrogen receptorantagonists or selective estrogen receptor modulators for exampletamoxifen, toremifene, droloxifene, faslodex or raloxifene; aromataseinhibitors such as exemestane, anastrozole, letrazole and vorozole;differentiating agents such as retinoids, vitamin D and retinoic acidmetabolism blocking agents (RAMBA) for example accutane; DNA methyltransferase inhibitors for example azacytidine; kinase inhibitors forexample flavoperidol, imatinib mesylate or gefitinib;farnesyltransferase inhibitors; or other HDAC inhibitors.

Preferred compounds of this invention include those found in the Tablesbelow:

TABLE I

—L—C(O)NHOH 4-hydroxyaminocarbonyl 5-hydroxyaminocarbonyl5-[(trans)-2-hydroxyamino-carbonylethen-1-yl

TABLE II

R 3,4-dimethoxyphenyl 4-trifluoromethoxyphenyl 4-methylphenyl4-trifluroromethylphenyl 4-nitrophenyl 4-acetylphenyl thiophen-2-ylbiphenyl 5-(N,N-dimethylamino)-naphthalenyl 4-fluorophenyl

TABLE III

R methyl benzyl 2-hydroxyethyl 2-aminoethyl 2-phenylethyl

TABLE IV

—L—C(O)NHOH 4-hydroxyaminocarbonyl

TABLE V

A homopiperazinyl

TABLE VI

R methyl phenyl benzyl

TABLE VII

Q methylene

Particularly preferred compounds include the following compounds andpharmaceutically acceptable salts thereof:

-   1-(2-naphthylsulfonyl)-4-(5-hydroxyaminocarbonylthiazol-2-yl)piperazine;-   1-(2-naphthylsulfonyl)-4-(5-hydroxyaminocarbonylthiazol-2-yl)-1,4-diazepane;-   1-(2-naphthylsulfonyl)-4-(4-hydroxyaminocarbonylthiazol-2-yl)piperazine;-   1-(2-naphthylsulfonyl)-4-[(5-(2-hydroxyaminocarbonylethen-1(E)-yl-thiazol-2-yl)piperazine;-   1-(phenylsulfonyl)-4-[(5-(2-hydroxyaminocarbonylethen-1(E)-yl-thiazol-2-yl)piperazine;-   1-(3,4-dimethoxyphenylsulfonyl)-4-[(5-(2-hydroxyaminocarbonylethen-1(E)-yl-thiazol-2-yl)piperazine;-   1-(4-methoxyphenylsulfonyl)-4-[(5-(2-hydroxyaminocarbonylethen-1(E)-yl-thiazol-2-yl)piperazine;-   1-(4-trifluoromethoxyphenylsulfonyl)-4-[(5-(2-hydroxyaminocarbonylethen-1(E)-yl-thiazol-2-yl)piperazine;-   1-(4-methylphenylsulfonyl)-4-[(5-(2-hydroxyaminocarbonylethen-1(E)-yl-thiazol-2-yl)piperazine;-   1-(4-trifluoromethylphenylsulfonyl)-4-[(5-(2-hydroxyaminocarbonylethen-1(E)-yl-thiazol-2-yl)piperazine;-   1-(4-nitrophenylsulfonyl)-4-[(5-(2-hydroxyaminocarbonylethen-1(E)-yl-thiazol-2-yl)piperazine;-   1-(thien-2-ylsulfonyl)-4-[(5-(2-hydroxyaminocarbonylethen-1(E)-yl-thiazol-2-yl)piperazine;-   1-(1,1′biphenylsulfonyl)-4-[(5-(2-hydroxyaminocarbonylethen-1(E)-yl-thiazol-2-yl)piperazine;-   1-(5-dimethylamino-naphthalene-1-sulfonyl)-4-[(5-(2-hydroxyaminocarbonylethen-1(E)-yl-thiazol-2-yl)piperazine;-   1-(4-fluorophenylsulfonyl)-4-[(5-(2-hydroxyaminocarbonylethen-1(E)-yl-thiazol-2-yl)piperazine;-   4-(2-naphthylsulfonylamino)-1-[(5-(2-hydroxyaminocarbonyl-thiazol-2-yl)-piperadine;-   4-(1,1′-biphenylsulfonylamino)-1-[(5-(2-hydroxyaminocarbonyl-thiazol-2-yl)-piperadine;-   4-(3,4-dimethoxyphenylsulfonylamino)-1-[(5-(2-hydroxyaminocarbonyl-thiazol-2-yl)-piperadine;-   4-(4-methylphenylsulfonylamino)-1-[(5-(2-hydroxyaminocarbonyl-thiazol-2-yl)-piperadine;-   2-(4-{[(1,1′-biphenylsulfonyl)amino]methyl}piperidin-1-yl)-1,3-thiazole-5-carboxylic    acid hydroxyamide;-   2-{[1-(2-naphthylsulfonyl)piperidin-4-yl]amino}-1,3-thiazole-5-carboxylic    acid hydroxyamide;-   2-(6-{[(4-methylphenyl)sulfonyl]amino}-3-azabicyclo[3.1.0]hex-3-yl)-1,3-thiazole-5-carboxylic    acid hydroxyamide;-   2-[3-[(4-methylphenyl)sulfonyl]tetrahydropyrimidin-1(2H)-yl]-1,3-thiazole-5-carboxylic    acid hydroxylamide;-   2-[4-(3,4-dimethoxy-benzene    sulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic acid hydroxyamide;-   2-[4-(4-trifluoromethoxy-benzene    sulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic acid hydroxyamide;-   2-[4-(4 toluene-4-sulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic    acid hydroxyamide;-   2-[4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic    acid hydroxyamide;-   2-[4-(4-nitro-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic    acid hydroxyamide;-   2-[4-(4-acetyl-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic    acid hydroxyamide;-   2-[4-(thiophene-2-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic    acid hydroxyamide;-   2-[4-(biphenyl-4-sulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic    acid hydroxyamide;-   2-[4-(5-dimethylamino-naphthalene-1-sulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic    acid hydroxyamide;-   2-[4-(4-fluoro-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic    acid hydroxyamide;-   2-(4-methyl-piperazin-1-yl)-thiazole-5-carboxylic acid hydroxyamide;-   2-(4-Benzyl-piperazin-1-yl)-thiazole-5-carboxylic acid hydroxyamide    (16b-hydroxamate);-   2-(4-(2-hydroxyethyl)-piperazin-1-yl)-thiazole-5-carboxylic acid    hydroxyamide;-   2-(4-(2-aminoethyl)-piperazin-1-yl)-thiazole-5-carboxylic acid    hydroxyamide;-   2-(4-phenylethyl -piperazin-1-yl)-thiazole-5-carboxylic acid    hydroxyamide;-   2-(4-(2-oxo-2-phenylethyl)piperazin-1-yl)-1,3-thiazole-5-carboxylic    acid hydroxyamide;-   2-(4-acetyl-piperazin-1-yl)-thiazole-5-carboxylic acid hydroxamide;-   2-(4-benzoyl-piperazin-1-yl)-thiazole-5-carboxylic acid hydroxamide;-   2-(4-phenylacetyl-piperazin-1-yl)-thiazole-5-carboxylic acid    hydroxamide;-   2-[4-(3-{1H-indol-3-yl}propanoyl)-piperazin-1-yl-1,3-thiazole-5-carboxylic    acid hydroxyamide;-   N-(2-naphthylsulfonyl)-N′-{2-[5-(N-hydroxycarboxamido)]thiazolyl}-piperazine;-   2-[1-(1,1′-biphenyl-4-ylsulfonyl)piperidin-4-yl]-1,3-thiazole-5-carboxylic    acid hydroxyamide;

and pharmaceutically acceptable salts, isomers, tautomers, and prodrugsthereof.

DETAILED DESCRIPTION OF THE INVENTION

As noted above, this invention is directed to compounds, pharmaceuticalcompositions and methods for inhibiting histone deacetylase (HDAC)enzymatic activity. However, prior to describing this invention in moredetail, the following terms will first be defined.

DEFINITIONS

Unless otherwise limited by a specific recitation herein, the followingterms have the following meanings;

“Alkyl” refers to monovalent alkyl groups having from 1 to 10 carbonatoms, preferably from 1 to 5 carbon atoms and more preferably 1 to 3carbon atoms. This term is exemplified by groups such as methyl, ethyl,n-propyl, iso-propyl, n-butyl, t-butyl, n-pentyl and the like.

“Substituted alkyl” refers to a monovalent alkyl group having from 1 to3, and preferably 1 to 2, substituents selected from the groupconsisting of alkoxy, substituted alkoxy, acyl, acylamino, amino,substituted amino, aminoacyl, aryl, substituted aryl, aryloxy,substituted aryloxy, cyano, halogen, hydroxyl, nitro, carboxyl, carboxylesters, cycloalkyl, substituted cycloalkyl, heteroaryl, substitutedheteroaryl, heterocyclic, and substituted heterocyclic.

“Alkylene” refers to divalent alkylene groups having from 1 to 10 carbonatoms, preferably from 1 to 5 carbon atoms and more preferably 1 to 3carbon atoms. This term is exemplified by groups such as methylene,ethylene, n-propylene (1,3-propylene), iso-propylene (1,2-propylene),n-butylene (1,4-butylene), n-pentylene (1,5-pentylene), and the like.

“Substituted alkylene” refers to a divalent alkylene group having from 1to 3, and preferably 1 to 2, substituents selected from the groupconsisting of alkoxy, substituted alkoxy, acyl, acylamino, amino,substituted amino, aminoacyl, aryl, substituted aryl, aryloxy,substituted aryloxy, cyano, halogen, hydroxyl, nitro, carboxyl, carboxylesters, cycloalkyl, substituted cycloalkyl, heteroaryl, substitutedheteroaryl, heterocyclic, and substituted heterocyclic.

“Alkoxy” refers to the group “alkyl-O—” which includes, by way ofexample, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, t-butoxy,sec-butoxy, n-pentoxy and the like.

“Substituted alkoxy” refers to the group “substituted alkyl-O—”.

“Acyl” refers to the groups H—C(O)—, alkyl-C(O)—, substitutedalkyl-C(O)—, alkenyl-C(O)—, substituted alkenyl-C(O)—, cycloalkyl-C(O)—,substituted cycloalkyl-C(O)—, aryl-C(O)—, substituted aryl-C(O)—,heteroaryl-C(O)—, substituted heteroaryl-C(O), heterocyclic-C(O)—, andsubstituted heterocyclic-C(O)—.

“Acylamino” refers to the group —C(O)NR¹⁰R¹⁰ where each R¹⁰ isindependently selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl,cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl,heterocyclic, substituted heterocyclic and where each R¹⁰ is joined toform together with the nitrogen atom a heterocyclic or substitutedheterocyclic ring.

“Alkenyl” refers to a monovalent alkenyl group having from 2 to 6 carbonatoms and more preferably 2 to 4 carbon atoms and having at least 1 andpreferably from 1-2 sites of alkenyl unsaturation. The term “alkenyl”encompasses any and all combinations of cis and trans isomers arisingfrom the presence of unsaturation.

“Substituted alkenyl” refers to alkenyl groups having from 1 to 3substituents, and preferably 1 to 2 substituents, selected from thegroup consisting of alkoxy, substituted alkoxy, acyl, acylamino, amino,substituted amino, aminoacyl, aryl, substituted aryl, aryloxy,substituted aryloxy, cyano, halogen, hydroxyl, nitro, carboxyl, carboxylesters, cycloalkyl substituted cycloalkyl, heteroaryl, substitutedheteroaryl, heterocyclic, and substituted heterocyclic provided that anyhydroxyl substitution is not on a vinyl carbon atom.

“Alkenylene” refers to a divalent alkenyl group having from 2 to 6carbon atoms and more preferably 2 to 4 carbon atoms and having at least1 and preferably from 1-2 sites of alkenyl unsaturation. The term“alkenylene” encompasses any and all combinations of cis and transisomers arising from the presence of unsaturation.

“Substituted alkenylene” refers to alkenylene groups having from 1 to 3substituents, and preferably 1 to 2 substituents, selected from thegroup consisting of alkoxy, substituted alkoxy, acyl, acylamino,acyloxy, amino, substituted amino, aminoacyl, aryl, substituted aryl,aryloxy, substituted aryloxy, cyano, halogen, hydroxyl, nitro, carboxyl,carboxyl esters, cycloalkyl, substituted cycloalkyl, heteroaryl,substituted heteroaryl, heterocyclic, and substituted heterocyclicprovided that any hydroxyl substitution is not on a vinyl carbon atom.

“Amino” refers to the group —NH₂.

“Substituted amino” refers to the group —NR′R″ where R′ and R″ areindependently selected from the group consisting of hydrogen, alkylsubstituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl,cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl,heterocyclic, substituted heterocyclic and where R′ and R″ are joined,together with the nitrogen bound thereto to form a heterocyclic orsubstituted heterocylic group provided that R′ and R″ are both nothydrogen. When R′ is hydrogen and R″ is alkyl, the substituted aminogroup is sometimes referred to herein as alkylamino. When R′ and R″ arealkyl, the substituted amino group is sometimes referred to herein asdialkylamino.

“Aminoacyl” refers to the groups —NR¹¹C(O)alkyl, —NR¹¹C(O)substitutedalkyl, —NR¹¹C(O)cycloalkyl, —NR¹¹C(O)substituted cycloalkyl,—NR¹¹C(O)alkenyl, —NR¹¹C(O)substituted alkenyl, —NR¹¹C(O)aryl,—NR¹¹C(O)substituted aryl, —NR¹¹C(O)heteroaryl, —NR¹¹C(O)substitutedheteroaryl, —NR¹¹C(O)heterocyclic, and —NR¹¹C(O)substituted heterocyclicwhere R¹¹ is hydrogen or alkyl.

“Aryl” or “Ar” refers to a monovalent aromatic carbocyclic group of from6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiplecondensed rings (e.g., naphthyl or anthryl) which condensed rings may ormay not be aromatic (e.g., 2-benzoxazolinone,2H-1,4-benzoxazin-3(4H)-one-7-yl, and the like) provided that the pointof attachment is to an aromatic ring atom. Preferred aryls includephenyl and naphthyl, e.g, 2-naphthyl.

“Substituted aryl” refers to aryl groups which are substituted with from1 to 3 substituents, and preferably 1 to 2 substituents, selected fromthe group consisting of hydroxy, acyl, acylamino, alkyl, substitutedalkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, amino,substituted amino, aminoacyl, aryl, substituted aryl, aryloxy,substituted aryloxy, cycloalkoxy, substituted cycloalkoxy, carboxyl,carboxyl esters, cyano, cycloalkyl, substituted cycloalkyl, halo, nitro,heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, heteroaryloxy, substituted heteroaryloxy, heterocyclyloxy,and substituted heterocyclyloxy.

“Aryloxy” refers to the group aryl-O— that includes, by way of example,phenoxy, naphthoxy, and the like.

“Substituted aryloxy” refers to substituted aryl-O— groups.

“Carboxyl” refers to —COOH or pharmaceutically acceptable salts thereof.

“Carboxyl esters” refers to the groups —C(O)O-alkyl, —C(O)O-substitutedalkyl, —C(O)O-aryl, and —C(O)O-substituted aryl wherein alkyl,substituted alkyl, aryl and substituted aryl are as defined herein.

“Cycloalkyl” refers to monovalent cyclic alkyl groups of from 3 to 10carbon atoms having single or multiple condensed rings which condensedrings may or may not be cycloalkyl provided that the point of attachmentis to a cycloalkyl ring atom. Examples of cycloalkyl groups include, byway of example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclooctyl and the like.

“Substituted cycloalkyl” refers to a cycloalkyl group, having from 1 to5 substituents selected from the group consisting of oxo (═O), thioxo(═S), alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl,acylamino, amino, substituted amino, aminoacyl, aryl, substituted aryl,aryloxy, substituted aryloxy, cyano, halogen, hydroxyl, nitro, carboxyl,carboxyl esters, cycloalkyl, substituted cycloalkyl, heteroaryl,substituted heteroaryl, heterocyclic, and substituted heterocyclic.

“Cycloalkenyl” refers to monovalent cyclic alkenyl groups of from 4 to10 carbon atoms, preferably 5 to 8 carbon atoms, having single ormultiple condensed rings which condensed rings may or may not becycloalkenyl provided that the point of attachment is to a cycloalkenylring atom. Examples of cycloalkenyl groups include, by way of example,cyclopenten-4-yl, cyclooctene-5-yl and the like.

“Substituted cycloalkenyl” refers to a cycloalkenyl group, having from 1to 5 substituents selected from the group consisting of oxo (═O), thioxo(═S), alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl,acylamino, amino, substituted amino, aminoacyl, aryl, substituted aryl,aryloxy, substituted aryloxy, cyano, halogen, hydroxyl, nitro, carboxyl,carboxyl esters, cycloalkyl, substituted cycloalkyl, heteroaryl,substituted heteroaryl, heterocyclic, and substituted heterocyclicprovided that any hydroxyl substitution is not on an ethylenic carbonatom.

“Cycloalkylene” refers to divalent cyclic alkyl groups of from 3 to 10carbon atoms having single or multiple condensed rings which condensedrings may or may not be cycloalkyl provided that the points ofattachment are to cycloalkyl ring atoms. Cycloalkylene rings include, byway of example, cyclopropylene, 1,2-cyclobutylene, 1,3-cyclopentylene,1,4-cyclooctylene, and the like. Cycloalkylene includes all cis andtrans isomers encompassed by the particular cycloalkylene group.

“Substituted cycloalkylene” refers to a cycloalkylene group, having from1 to 5 substituents selected from the group consisting of oxo (═O),thioxo (═S), alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl,acylamino, amino, substituted amino, aminoacyl, aryl, substituted aryl,aryloxy, substituted aryloxy, cyano, halogen, hydroxyl, nitro, carboxyl,carboxyl esters, cycloalkyl, substituted cycloalkyl, heteroaryl,substituted heteroaryl, heterocyclic, and substituted heterocyclic.

“Cycloalkoxy” refers to —O-cycloalkyl groups.

“Substituted cycloalkoxy” refers to —O-substituted cycloalkyl groups.

“Halo” or “halogen” refers to fluoro, chloro, bromo and iodo andpreferably is fluoro or chloro.

“Heteroaryl” refers to a monovalent aromatic group of from 1 to 15carbon atoms, preferably from 1 to 10 carbon atoms, and 1 to 4heteroatoms selected from the group consisting of oxygen, nitrogen, —S—,—SO—, and —SO₂— within the ring. Such heteroaryl groups can have asingle ring (e.g., pyridyl or furyl) or multiple condensed rings (e.g.,indolizinyl or benzothienyl) provided that the point of attachment isthrough a heteroaryl ring atom. Preferred heteroaryls include pyridyl,pyrrolyl, indolyl, thiophenyl, and furyl.

“Substituted heteroaryl” refers to heteroaryl groups that aresubstituted with from 1 to 3 substituents selected from the same groupof substituents defined for substituted aryl.

“Heteroaryloxy” refers to the group —O-heteroaryl and “substitutedheteroaryloxy” refers to the group —O-substituted heteroaryl.

“Heterocycle” or “heterocyclic” refers to a monovalent saturated orunsaturated group having a single ring or multiple rings, includingfused rings, spiro rings, bicyclic rings, and rings connected by an “exosingle bond,” from 1 to 10 carbon atoms and from 1 to 4 hetero atomsselected from the group consisting of nitrogen, sulfur, —S(O)—, —S(O)₂—,or oxygen within the ring wherein, in fused ring systems, one or morethe rings can be aryl or heteroaryl provided that the point ofattachment is to a heterocyclic (non-aromatic) ring atom. In additionone or more carbon atoms within the ring may contain an oxo (═O) or athioxo (═S) group.

“Exo-single bond” refers to a bond between two heterocycle orheterocyclic rings, as exemplified as follows, wherein the bond betweenA and B is an exo-single bond:

“Heterocyclene” refers to a divalent saturated or unsaturated grouphaving a single ring or multiple condensed rings, from 1 to 10 carbonatoms and from 1 to 4 hetero atoms selected from the group consisting ofnitrogen, sulfur or oxygen within the ring wherein, in fused ringsystems, one or more the rings can be aryl or heteroaryl.

“Substituted heterocyclene” refers to heterocyclene groups that aresubstituted with from 1 to 3 of the same substituents as defined forsubstituted cycloalkylene.

Examples of heterocycles and heteroaryls include, but are not limitedto, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine,pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole,indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine,naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine,carbazole, carboline, phenanthridine, acridine, phenanthroline,isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine,imidazolidine, imidazoline, piperidine, piperazine, indoline,phthalimide, 1,2,3,4-tetrahydro-isoquinoline,4,5,6,7-tetrahydro-benzo[b]thiophene, thiazole, thiazolidine, thiophene,benzo[b]thiophene, morpholinyl, thiomorpholinyl (also referred to asthiamorpholinyl), piperidinyl, pyrrolidine, tetrahydrofuranyl, and thelike.

“Heterocyclyloxy” refers to the group —O-heterocyclic and “substitutedheterocyclyloxy” refers to the group —O-substituted heterocyclic.

The term “cyclo” refers to an cycloalkyl ring of from 3 to 7 carbonatoms. The “cyclo” ring may optionally contain 1 or 2 points ofunsaturation within the ring and the ring is optionally substituted withfrom about 1 to about 3 substituents selected from the group consistingof alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl,heterocyclic, substituted heterocyclic, aryl, substituted aryl,heteroaryl, substituted heteroaryl, and the like. The cycloalkyl ringmay also have one or two of the carbon atoms in the ring replaced bya >C═O or by >C═S moiety.

The term “het” refers to a heterocyclic ring of from 3 to 7 carbon atomsand from 1 to 4 hetero atoms selected from N, O and S. The heterocyclicring may optionally contain 1 or 2 points of unsaturation within thering and the ring is optionally substituted with from about 1 to about 3substituents selected from the group consisting of alkyl, substitutedalkyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substitutedheterocyclic, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, and the like. The heterocyclic ring may also have one or twoof the carbon atoms in the ring replaced by a >C═O or by >C═S moiety.

The terms “-het-(L²)_(b)-het-”, “-het-(L²)_(b)-cyclo-”,“-cyclo-(L²)_(b)-het-” and “-cyclo-(L²)_(b)-cyclo-” refer to anycombinations of “het” and “cyclo” groups linked together by a linker(when b is 1) selected from the group consisting of a bond, alkylene,substituted alkylene, alkenylene, and substituted alkenylene,cycloalkylene, and substituted cycloalkylene. When b is 0, thecombinations of het and cyclo include multicyclic groups (of from 1 to 3rings) wherein the rings may be fused multicyclic rings, or spirocyclicrings.

“Pharmaceutically acceptable salt” refers to pharmaceutically acceptablesalts of a compound of Formula I which salts are derived from a varietyof organic and inorganic counter ions well known in the art and include,by way of example only, sodium, potassium, calcium, magnesium, ammonium,tetraalkylammonium, and the like; and when the molecule contains a basicfunctionality, salts of organic or inorganic acids, such ashydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate,oxalate and the like.

“Tautomers” refers to structures which are art recognized to be inequilibrium with the depicted structure. For example, 1,2,4-imidazolehas the following tautomeric structures:

all of which are art recognized.

The term “platinum coordination compound” is used herein to denote anytumor cell growth inhibiting platinum coordination compound whichprovides platinum in the form of an ion.

The term “taxane compounds” indicates a class of compounds having thetaxane ring system and related to or derived form extracts from certainspecies of yew (Taxus) trees.

The term “topisomerase inhibitors” is used to indicate enzymes that arecapable of altering DNA topology in eukaryotic cells. They are criticalfor important cellular functions and cell proliferation. There are twoclasses of topoisomerases in eukaryotic cells, namely type I and typeII. Topoisomerase I is a monomeric enzyme of approximately 100,000molecular weight. The enzyme binds to DNA and introduces a transientsingle-strand break, unwinds the double helix (or allows it to unwind)and subsequently reseals the break before dissociating from the DNAstrand. Topisomerase II has similar mechanism of action which involvesthe introduction of DNA strand breaks of the formation of free radicals.

The term “camptothecin compounds” is used to indicate compounds that arerelated to or derived from the parent camptothecin compound which iswater-insoluble alkaloid derived from the Chinese tree Camptothecinacuminate and the Indian tree Nothapodytes foetida.

The term “podophyllotoxin compounds” is used to indicate compounds thatare related to or derived from the parent podophyllotoxin, which isextracted from the mandrake plant.

The term “anti-tumour vinca alkaloids” is used to indicate compoundsthat are related to or derived from extracts of the periwinkle plant(Vinca rosea).

The term “alkylating agents” encompass a divers group of chemicals thathave the common feature that they have the capacity to contribute, underphysiological conditions, alkyl groups to biologically vitalmacromolecules such as DNA. With most of the more important agents suchas the nitrogen mustards and the nitrosoureas, the active alkylatingmoieties are generated in vivo after complex degradative reactions, someof which are enzymatic. The most important pharmacological actions ofthe alkylating agents are those that disturb the fundamental mechanismsconcerned with cell proliferation in particular DNA synthesis and celldivision. The capacity of alkylating agents to interfere with DNAfunction and integrity in rapidly proliferating tissues provides thebasis for their therapeutic applications and for many of their toxicproperties.

The term “anti-tumour anthracycline derivatives” comprise antibioticsobtained from the fungus Strep. peuticus var. caesius and theirderivatives, characterized by having a tetracycline ring structure withan unusual sugar, daunosamine, attached by a glycosidic linkage.

Amplification of the human epidermal growth factor receptor 2 protein(HER 2) in primary breast carcinomas has been shown to correlate with apoor clinical prognosis for certain patients. Trastuzumab is highlypurified recombinant DNA-derived humanized monoclonal IgG1 kappaantibody that binds with high affinity and specificity to theextracellular domain of the HER2 receptor.

Many breast cancers have estrogen receptors and growth of these tumorscan be stimulated by estrogen. The terms “estrogen receptor antagonists”and “selective estrogen receptor modulators” are used to indicatecompetitive inhibitors of estradiol binding to the estrogen receptor(ER). Selective estrogen receptor modulators, when bound to the ER,induces a change in the three-dimensional shape of the receptor,inhibiting its binding to the estrogen responsive element (ERE) on DNA.

In postmenopausal women, the principal source of circulating estrogen isfrom conversion of adrenal and ovarian androgens (androstenedione andtestosterone) to estrogens (estrone and estradiol) by the aromataseenzyme in peripheral tissues. Estrogen deprivation through aromataseinhibition or inactivation is an effective and selective treatment forsome postmenopausal patients with hormone-dependent breast cancer.

The term “antiestrogen agent” is used herein to include not onlyestrogen receptor antagonists and selective estrogen receptor modulatorsbut also aromatase inhibitors as discussed above.

The term “differentiating agents” encompass compounds that can, invarious ways, inhibit cell proliferation and induce differentiation.Vitamin D and retinoids are known to play a major role in regulatinggrowth and differentiation of a wide variety of normal and malignantcell types. Retinoic acid metabolism blocking agents (RAMBA's) increasethe levels of endogenous retinoic acids by inhibiting the cytochromeP450-mediated catabolism of retinoic acids.

DNA methylation changes are among the most common abnormalities in humanneoplasia. Hypermethylation within the promoters of selected genes isusually associated with inactivation of the involved genes. The term“DNA methyl transferase inhibitors” is used to indicate compounds thatact through pharmacological inhibition of DNA methyl transferase andreactivation of tumour suppressor gene expression.

The term “kinase inhibitors” comprises potent inhibitors of kinases thatare involved in cell cycle progression and programmed cell death(apoptosis).

The term “farnesyltransferase inhibitors” is used to indicate compoundsthat were designed to prevent farnesylation of Ras and otherintracellular proteins. They have been shown to have effect on malignantcell proliferation and survival.

Compound Preparation

The compounds of this invention can be prepared from readily availablestarting materials using the following general methods and procedures.It will be appreciated that where typical or preferred processconditions (i.e., reaction temperatures, times, mole ratios ofreactants, solvents, pressures, etc.) are given, other processconditions can also be used unless otherwise stated. Optimum reactionconditions may vary with the particular reactants or solvent used, butsuch conditions can be determined by one skilled in the art by routineoptimization procedures.

Additionally, as will be apparent to those skilled in the art,conventional protecting groups may be necessary to prevent certainfunctional groups from undergoing undesired reactions, Suitableprotecting groups for various functional groups as well as suitableconditions for protecting and deprotecting particular functional groupsare well known in the art. For example, numerous protecting groups aredescribed in T. W. Greene and G. M. Wuts, Protecting Groups in OrganicSynthesis, Third Edition, Wiley, New York, 1999, and references citedtherein.

Furthermore, the compounds of this invention will typically contain oneor more chiral centers. Accordingly, if desired, such compounds can beprepared or isolated as pure stereoisomers, i.e., as individualenantiomers or diastereomers, or as stereoisomer-enriched mixtures. Allsuch stereoisomers (and enriched mixtures) are included within the scopeof this invention, unless otherwise indicated. Pure stereoisomers (orenriched mixtures) may be prepared using, for example, optically activestarting materials or stereoselective reagents well-known in the art.Alternatively, racemic mixtures of such compounds can be separatedusing, for example, chiral column chromatography, chiral resolvingagents and the like.

Still fiber, some of the compounds defined herein include vinyl groupswhich can exist in cis, trans or a mixture of cis and trans forms. Allcombinations being within the scope of this invention.

The starting materials for the following reactions are generally knowncompounds or can be prepared by known procedures or obviousmodifications thereof. For example, many of the starting materials areavailable from commercial suppliers such as Aldrich Chemical Co.(Milwaukee, Wis., USA), Bachem (Torrance, Calif., USA), Emka-Chemce orSigma (St. Louis, Mo., USA). Others may be prepared by procedures, orobvious modifications thereof, described in standard reference textssuch as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15(John Wiley and Sons, 1991), Rodd's Chemistry of Carbon Compounds,Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989),Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March'sAdvanced Organic Chemistry, (John Wiley and Sons, 4^(th) Edition), andLarock's Comprehensive Organic Transformations (VCH Publishers Inc.,1989).

As to the synthesis of compounds of this invention, Scheme 1 belowillustrates a general method for synthesis wherein L is a covalent bond,X is N and Y is CH, and the ring defined by A contains two ring aminogroups.

where X′ is a halogen such as bromo or chloro, one of R²¹ and R²² is—C(O)OPg where Pg is a carboxyl protecting group such as an alkyl group,e.g., methyl and the other is hydrogen, and R, R² and z are as definedabove. For illustrative purposes in the discussion below, z will beassigned the value 1, R²¹ will be carboxy methyl ester (—COOCH₃), andR²² will be hydrogen. It is understood, of course, that otherdiaminoheterocycles such as where z is zero or one and other thiazolecompounds can similarly be employed.

Specifically, commercially available methyl 2-halo-5-carboxylthiazole,compound 30, is condensed with at least an equivalent and preferably andexcess of mono-protected 1-t-butoxycarbonyl (Boc) piperazine, compound31, under conventional conditions to provide for methyl2-[(1-t-butoxycarbonyl)piperazin-4-yl]-5-carboxylthiazole, compound 32.The reaction is typically conducted in an inert solvent such asacetonitrile, chloroform, and the like in the presence of a suitablebase such as potassium carbonate which scavenges the acid generatedduring the reaction. The reaction is typically conducted at an elevatedtemperature of from about 40° to 100° C. for a period of time sufficientfor substantial completion of the reaction which typically occurs withinabout 2 to 48 hours. The resulting product, compound 32, can berecovered by conventional methods, such as chromatography, filtration,crystallization, evaporation and the like or, alternatively, used in thenext step without purification and/or isolation.

Conventional deprotection of the Boc-protected amino group (e.g., TFA)of methyl 2-[(1-t-butoxycarbonyl)piperazin-4-yl]-5-carboxylthiazole,compound 32, provides for the corresponding methyl2-(piperazin-4-yl)-5-carboxylthiazole, not shown, which is then reactedwith a suitable sulfonyl chloride (RSO₂Cl) to provide for thecorresponding sulfonyl amide, compound 33. This latter reaction istypically conducted by combining preferably from about 1.5 to about 2.5equivalents, of the sulfonyl chloride in an inert diluent such asdichloromethane and the like. Generally, the reaction is conducted at atemperature ranging from about 0° C. to about 40° C. for about 1 toabout 24 hours. Preferably, this reaction is conducted in the presenceof a suitable base to scavenge the acid generated during the reaction.Suitable bases include, by way of example, tertiary amines, such astriethylamine, diisopropylethylamine, N-methylmorpholine and the like.Alternatively, the reaction can be conducted under Schotten-Baumann-typeconditions using aqueous alkali, such as sodium hydroxide and the like,as the base. Upon completion of the reaction, the resulting N-sulfonylamino acid, compound 33 is recovered by conventional methods includingneutralization, extraction, precipitation, chromatography, filtration,evaporation and the like.

The sulfonyl chlorides employed in the above reaction are either knowncompounds or compounds that can be prepared from known compounds byconventional synthetic procedures. Such compounds are typically preparedfrom the corresponding sulfonic acid, i.e., from compounds of theformula RSO₃H where R is as defined above, using phosphorous trichlorideand phosphorous pentachloride. This reaction is generally conducted bycontacting the sulfonic acid with about 2 to 5 molar equivalents ofphosphorous trichloride and phosphorous pentachloride, either neat or inan inert solvent, such as dichloromethane, at temperature in the rangeof about 0 to about 80° C. for about 1 to about 48 hours to afford thesulfonyl chloride. Alternatively, the sulfonyl chlorides can be preparedfrom the corresponding thiol compound, i.e., from compounds of theformula R—SH where R is as defined herein, by treating the thiol withchlorine (Cl₂) and water under conventional reaction conditions.

Examples of sulfonyl chlorides suitable for use in this inventioninclude, but are not limited to, methanesulfonyl chloride,2-propanesulfonyl chloride, 1-butanesulfonyl chloride, benzenesulfonylchloride, 1-naphthalenesulfonyl chloride, 2-naphthalenesulfonylchloride, p-toluenesulfonyl chloride, 0.2-methylphenylsulfonyl chloride,4 acetamidobenzenesulfonyl chloride, 4-tert-butylbenzenesulfonylchloride, 4 bromobenzenesulfonyl chloride, 2-carboxybenzenesulfonylchloride, 4-cyanobenzenesulfonyl chloride, 3,4-dichlorobenzenesulfonylchloride, 3,5-dichlorobenzenesulfonyl chloride,3,4-dimethoxybenzenesulfonyl chloride,3,5-ditrifluoromethylbenzenesulfonyl chloride, 4-fluorobenzenesulfonylchloride, 4-methoxybenzenesulfonyl chloride,2-methoxycarbonylbenzenesulfonyl chloride, 4-methylamidobenzenesulfonylchloride, 4-nitrobenzenesulfonyl chloride, 4-thioamidobenzenesulfonylchloride, 4-trifluoromethyl-benzenesulfonyl chloride,4-trifluoromethoxybenzenesulfonyl chloride,2,4,6-trimethylbenzenesulfonyl chloride, 2-phenylethanesulfonylchloride, 2-thiophenesulfonyl chloride, 5-chloro-2-thiophenesulfonylchloride, 2,5-dichloro-4-thiophenesulfonyl chloride, 2-thiazolesulfonylchloride, 2-methyl-4-thiazolesulfonyl chloride,1-methyl-4-imidazolesulfonyl chloride, 1-methyl-4-pyrazolesulfonylchloride, 5-chloro-1,3-dimethyl-4-pyrazolesulfonyl chloride,3-pyridinesulfonyl chloride, 2-pyrimidinesulfonyl chloride and the like.If desired, a sulfonyl fluoride, sulfonyl bromide or sulfonic acidanhydride may be used in place of the sulfonyl chloride in the abovereaction to form the N-sulfonyl amino acids.

The R²¹ methyl carboxyl group of compound 33 can then be converted to avariety of amides including hydroxyamides by reaction with a 2-20 foldexcess of a suitable amine such as hydroxylamine. The reaction istypically conducted in a suitable diluent such as a 5:2 mixture ofmethanol to water under basic conditions, e.g, the addition of sodiumhydroxide. The reaction is typically conducted at a temperature of fromabout −20° to 20° C. for a period of time sufficient for substantialcompletion of the reaction which typically occurs within about 0.5 to 10hours. The resulting amide, compound 34, can be recovered byconventional methods, such as chromatography, filtration,crystallization, evaporation and the like.

Alternatively, ester 33 is converted to the hydroxamic acid 34 as shownin Scheme 1B.

where HX is a strong acid and MOH is an alkali metal hydroxide.

The ester prepared by the methods of Scheme 1 is hydrolyzed to acarboxylic acid 33′ with about 1-20 equivalents of an alkali metalhydroxide such as, but not limited to, sodium hydroxide or potassiumhydroxide in a mixture of water and a suitable organic solvent in aboutone to 48 hours at about 20 to 100° C. Suitable organic solventsinclude, but are not limited to, tetrahydrofuran, ethanol, methanol, ordioxane. The reaction mixture is neutralized with an inorganic acid suchas hydrochloric, hydrobromic, or sulfuric acid and the solvents areevaporated. The residue is suspended in a suitable solvent and treatedwith about one to five equivalents of a tertiary amine such as, but notlimited to, triethylamine or diisopropyletoelamine (DIEA) about one tofive equivalents of N-hydroxybenzotriazole (HOBT) and about one to fiveequivalents of a carbodiimide coupling reagent such as, but not limitedto, dicyclohexylcarbodiimide or1-[3-(dimethylamino)propyl]-1-ethylcarbodiimide (EDC) and about one tofive equivalents of O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (NH₂OTHP)for about one to 48 hours at about 20 to 100° C. to produce a protectedhydroxamic acid 33″ A solution of about 1 to 50% strong acid such as,but not limited to, hydrochloric acid or trifluoroacetic acid in anorganic solvent such as, but not limited to, dichloromethane,dichloroethane, methanol, ethanol, or dioxane at about 0° to 80° C. inabout one minute to 24 hours converts 33″ to the hydroxamic acid 34 thatis recovered by the means previously described.

Scheme 1C shows the synthesis of compounds of formula I where T is abond and where R, R², R²¹, R²², Boc, X′ and z are as defined above.

Specifically, commercially available methyl 2-halo-5-carboxylthiazole,compound 30, is condensed with at least an equivalent and preferably anexcess of a mono-N-substituted piperazine 1C.1 under conventionalconditions to provide for a methyl2-[(1-substituted)piperazin-4-yl]-5-carboxylthiazole, 1C.2. The reactionis typically conducted in an inert solvent such as acetonitrile,chloroform, and the like in the presence of a suitable base such aspotassium carbonate that scavenges the acid generated during thereaction.

where R, R², R²¹, R²², Boc, X′ and z are as defined above.

Specifically, in Scheme 2, compound 32 is prepared as per Scheme 1above. Conventional removal of the Bloc group provides for the freeamino group on the piperazine ring (not shown). The amino group is thenacylated by conventional means such as reaction with an excess of theacid chloride, RC(O)Cl, in a suitable inert diluent such asdichloromethane and preferably in the presence of an tertiary amine toscavenge the acid generated during the reaction. Alternatively, the freeamine group of the piperazine is treated with about one to fiveequivalents of a carboxylic acid in the presence of a suitablecarbodiimide coupling reagent such as, but not limited to, EDCI ordicyclohexylcarbodiimide in the presence of about one to fiveequivalents of HOBT or HOAT and about one to five equivalents of atertiary amine base such as, but not limited to, diisopropylethylamineor triethylamine in a suitable solvent such as tetrahydrofuran ormethylene chloride at about 0 to 60° C. for about one to 72 hours. Theresulting amide, compound 35, can be recovered by conventional methods,such as chromatography, The reaction is typically conducted at anelevated temperature of from about 40° to 100° C. for a period of timesufficient for substantial completion of the reaction that typicallyoccurs within about 2 to 48 hours. The resulting product, compound 1C.2,can be recovered by conventional methods, such as chromatography,filtration, crystallization, evaporation and the like or, alternatively,used in the next step without purification and/or isolation. The R²¹methyl carboxylate group of IC.2 is then converted to a variety ofamides including hydroxyamides 1C.3 by any of the methods described forScheme 1.

Alternatively, compound 32 in Scheme 1 is deprotected as described aboveand the secondary nitrogen of the piperazine ring of the resultingproduct is alkylated with about one to five equivalents of an alkyl orsubstituted alkyl halide in a suitable solvent at about 0 to 100° C. inthe presence of about one to five equivalents of an alkali metalcarbonate in about one to 72 hours. Suitable alkyl and substituted alkylhalides include chlorides, bromides, and iodides. Suitable solvents are,but are not limited to, methylene chloride, tetrahydrofuran, dioxane,and dimethylformamide. Preferred alkali metal carbonates are potassiumand cesium carbonate. The resulting ester 1C.4 is converted to thedesired amides such as 1C.3 by any of the methods described above.

Scheme 2 illustrates the synthesis of compounds of formula I where T isa carbonyl group.

filtration, crystallization, evaporation and the like. Conversion of theamide 35 to compound 36 proceeds in the manner described above.

In Schemes 1 and 2, replacement of 4-Boc-piperazine with mono-aminoprotected diamino compounds provides for compounds of formula I such asthose where Q is amino, T is a sulfonylamide, etc. Examples ofcommercially available diamino compounds include 1,4-diaminocyclohexane,1,2-diaminocyclohexane, 4-aminopiperidine, 3-aminopiperidine,3-aminopyrrolidine, 4-(aminomethyl)piperidine,2-(aminomethyl)pyrrolidine, and the like. These compounds can beconventionally mono-amino protected to provide for suitable reagents foruse in this invention.

Scheme 3 illustrates the synthesis of compounds of formula I where L isan alkenylene group.

where X′, R and Boc are as defined above.

Specifically, commercially available 2-bromo-5-formylthiazole, compound37, is condensed with at least an equivalent and preferably and excessof mono-protected 1-t-butoxycarbonyl (Boc) piperazine, compound 31, asdescribed above to provide for methyl2-[(1-t-butoxycarbonyl)piperazin-4-yl]-5-formylthiazole, compound 38.Alternatively, 2-bromo-5-formylthiazole can be prepared from the5-carboxyl precursor, compound 30 where R²¹ is carboxyl or a carboxylester, by conventional reduction procedures.

Conversion of compound 38 to compound 39 proceeds via a conventionalWittig Horner reaction.

Removal of the Boc protecting group proceeds via conventional conditionsto provide for the free amine, not shown, which is then contacted withan excess of sulfonyl chloride in the manner described above to providefor compound 40. Conversion of the methyl ester of compound 40 to thecorresponding amide, e.g., hydroxylamide, proceeds via contacting theester with an excess of amine in the manner described above therebyproviding for compound 41.

In one alternative embodiment, commercially available2-bromo-4-formylthiophene or 2-bromo-5-formylthiophene can be employedin the reactions recited above to provide for thiophene compounds thecorresponding to thiazole compound 41.

In another alternative embodiment, the sulfonyl chloride, RSO₂Cl, can bereplaced with an acid chloride, RC(O)Cl, to provide for compounds whereT is carbonyl.

Still further, conventional oxidation of the sulfur in the thiophene orthe thiazolyl to the corresponding sulfoxide or sulfone proceeds, forexample, by contact with m-chloroperbenzoic acid.

In yet another embodiment, the vinylene group of compound 40 can beconverted to a cyclopropylene moiety by conventional reaction with atleast an equivalent and preferably an excess of diazomethane (CH₂N₂) inthe presence of a palladium diacetate as in Scheme 3A below:

Subsequent conversion of the carboxyl ester to the hydroxylamideproceeds as discussed above.

Scheme 4 illustrates the synthesis of compounds of formula I where Q isan alkylene group. For illustrative purposes, T is a sulfonyl group, thering defined by A is a piperazine ring, and W is S, X is N and Y is CH.

where R and Boc are as defined above.

Specifically, an excess of sulfonyl chloride, RSO₂Cl, is combined in themanner described above with 1-t-butoxycarbonylpiperazine, compound 31,to provide 4(RSO₂—)-1-t-butoxycarbonylpiperazine (not shown).Conventional removal of the Boc protecting group provides for4-(RSO₂—)-piperazine, compound 42.

Coupling of compound 42 with an ω-halocarboxylamide, illustrated by2-bromoacetamide, provides for compound 43. This conventional couplingreaction is preferably conducted in an inert solvent such as methanol,ethanol, and the like preferably in the presence of a suitable base suchas potassium carbonate to scavenge the acid generated during reaction.The reaction is preferably conducted at an elevated temperature of fromabout 50 to about 100° C. The reaction is continued until substantialcompletion which typically occurs within a period of from about 2 to 48hours. Upon completion of the reaction, compound 34 is recovered byconventional methods including neutralization, extraction,precipitation, chromatography, filtration, evaporation and the like or,alternatively, is used in the next step without isolation and/orpurification.

The amide of compound 43 is converted to the corresponding thioamide byconventional methods including reaction with P₂S₅ to provide forcompound 44 which can be recovered by conventional methods includingneutralization, extraction, precipitation, chromatography, filtration,evaporation and the like or, alternatively, is used in the next stepwithout isolation and/or purification

Compound 44 is converted to the corresponding thiazole derivative byreaction with methyl 2-chloro-2-formyl acetate, compound 45. In turn,this compound is prepared by reaction of methyl 2-chloroacetate andmethyl formate in the presence of a suitable base. Cyclization providesfor the 5-carboxylate (methyl ester) of the thiazole.

In scheme 4, the 5-carboxylate is converted to the correspondinghydroxylamide in the manner described above. It is understood, ofcourse, that this carboxylate can be reduced to the corresponding formylgroup via conventional reduction conditions well known in the art andthen used in the manner of Scheme 3 to provide for the alkenylenelinking group.

Compounds in Scheme 4 can be used to prepare similar compounds offormula I where T is a carbonyl group. For example, retention of the Bocprotecting group throughout this reaction scheme allows for thesynthesis of a Boc protected equivalent to compound 46. Removal of theBoc group followed by reaction with an acid chloride, RC(O)Cl, providesfor a carbonyl equivalent of compound 46 which can then be converted tothe corresponding N-hydroxylamide.

Scheme 4′ shows the synthesis of compounds of formula I where Q is acarbon-carbon bond between the ring defined by A and V. For illustrativepurposes, T is a sulfonyl group, the ring defined by A is a piperidinering, and W is S, X is N and Y is CH.

A Boc protected 4-(aminocarbothioyl)tetrahydropyridinle-1(2H)carboxylate4′.1 is treated with about one to 20 equivalents of methylchloro(formyl)acetate in a suitable solvent at about 0 to 140° C. forabout 30 minutes to 72 hours to give thiazole ester 4′.2. Suitablesolvents include, but are not limited to, methylene chloride, toluene,dioxane, tetrahydrofuran, and dimethylformamide. The Boc group of 4′.2is cleaved by any of the methods described above to give piperidine4′.3. Piperidine 4′.3 is sulfonylated by any of the methods describedabove to give sulfonylated piperidine 4′.4. Sulfonylated piperidine 4′.4is converted to hydroxamate 4′.5 by any of the methods described above.

Still further, other 5 membered heteroaryl ring systems for use in thisinvention can be readily prepared by conventional means as shown inSchemes 4A and 4B below:

Specifically, in Scheme 4A, ethyl 2-thiol-5-carboxylimidazole compound48, is converted to the corresponding methyl sulfone, compound 49,prepared by methylation using methyl iodide, followed by oxidation usingmetachloroperbenzoic acid. Subsequent re-esterification and reactionwith piperazine provides for compound 50 which can be used in theprocedures set forth above to provide for compounds of this invention.For example, conversion of the ethyl carboxylate to the formylfunctionality proceeds via well documented reduction procedures. Theformyl functionality can then be employed in a Wittig Horner reaction toprovide for the vinylene carboxylate derivative in the manner describedin Scheme 3 above.

Still further, Scheme 4B illustrates how commercially available2-amino-5-carboxyl-1,3,4-triazole can be converted into intermediateswhich can be used in the above schemes for the synthesis of compounds ofthis invention.

Compound 51 can be converted via conventional methods to thecorresponding 2-bromo-5-carboxyl-1,3,4-triazole or the2-(4-Boc-piperazin-1-yl)-5-carboxyl-1,3,4-triazole.

Still other heteroaryls useful in the synthetic schemes recited hereininclude the following commercially available compounds:

Compounds where Q is —SO₂—, V, Y and Z are carbon, X is S, W is O, andring A is piperidine are prepared using methods described in T. Hamadaet al Synthesis, 1986, 852 and shown in Scheme 5 below. This preparationis also useful for any A ring containing a nitrogen atom that may bebound to the sulfonyl group.

Compound 63, is an intermediate that, after deprotection, can beconverted to various analogs as exemplified herein.

For example, compound 60 in Scheme 5 above can be converted to compound61 by using the methods described in T. Hamada et al Synthesis, 1986,852. Coupling of the sulfonyl chloride, compound 61, with compound 62 isaccomplished as discussed herein above (see for example Scheme 4).

In Scheme 6 below, compounds where Q is —O—, V, Y and Z are carbon, X isS, W is O, and ring A is piperidine are prepared using methods describedherein and methods described in W. Huang et al. Biorg. Med. Chem. Lett.2003, 13 (3) 561. This preparation is also useful for any A ringcontaining at least one carbon atom that may be bound to the oxygenlinking the A ring to the 5-membered heteroaryl ring.

For example, compound 60 is reacted with compound 64 by reaction withtriphenylphospine and DEAD in an inert solvent such as THF. Again,intermediate 65, after deprotection, can be converted to various analogsas exemplified herein.

Compounds where Q is —O—, V, Y and Z are carbon, X is S, W is C(O), andring A is piperidine are prepared as discussed in Morimoto et al. J.med. Chem. 2001, 44 (21) 3369. This preparation is also useful for any Aring containing at least one carbon atom that may be bound to thecarbonyl linking the A ring to the 5-membered heteroaryl ring.

For Example, compound 60 is carboxylated with butyl lithium and carbondioxide to form compound 66. Reaction of compound 66 with mono-protectedpiperazine in the presence of a coupling agent, such as DCC, affordscompound 67, which after deprotection, can be converted to variousanalogs as exemplified herein.

Pharmaceutical Formulations

When employed as pharmaceuticals, the compounds of this invention areusually administered in the form of pharmaceutical compositions. Thesecompounds can be administered by a variety of routes including oral,rectal, transdermal, subcutaneous, intravenous, intramuscular, andintranasal. These compounds are effective as both injectable and oralcompositions. Such compositions are prepared in a manner well known inthe pharmaceutical art and comprise at least one active compound.

This invention also includes pharmaceutical compositions which contain,as the active ingredient, one or more of the compounds of formula I-VIIabove associated with pharmaceutically acceptable carriers. In makingthe compositions of this invention, the active ingredient is usuallymixed with an excipient, diluted by an excipient or enclosed within sucha carrier which can be in the form of a capsule, sachet, paper or othercontainer. The excipient employed is typically an excipient suitable foradministration to human subjects or other mammals. When the excipientserves as a diluent, it can be a solid, semi-solid, or liquid material,which acts as a vehicle, carrier or medium for the active ingredient.Thus, the compositions can be in the form of tablets, pills, powders,lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions,syrups, aerosols (as a solid or in a liquid medium), ointmentscontaining, for example, up to 10% by weight of the active compound,soft and hard gelatin capsules, suppositories, sterile injectablesolutions, and sterile packaged powders.

In preparing a formulation, it may be necessary to mill the activecompound to provide the appropriate particle size prior to combiningwith the other ingredients. If the active compound is substantiallyinsoluble, it ordinarily is milled to a particle size of less than 200mesh. If the active compound is substantially water soluble, theparticle size is normally adjusted by milling to provide a substantiallyuniform distribution in the formulation, e.g. about 40 mesh.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate, and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

The compositions are preferably formulated in a unit dosage form. Theterm “unit dosage forms” refers to physically discrete units suitable asunitary dosages for human subjects and other mammals, each unitcontaining a predetermined quantity of active material calculated toproduce the desired therapeutic effect, in association with a suitablepharmaceutical excipient.

The compounds of the present invention maybe administered to patientseither alone or in combination with other known anti-tumor agents. Whenadministered alone about 0.005 to about 100 mg/kg, more preferably about0.005 to about 10 mg/kg, are administered to the patient Higher andlower dosages may be used. Administration may occur once a day, orseveral times in a day. In addition the treatment may be repeated every7, 14, 21 or 28 days.

When administered in combination with other anti-cancer agents, thecompounds of the present invention may be prepared in a formulation thatincludes both the compounds of Formula I-VII and one or more otheranti-cancer agents. Alternatively the other anti-cancer agents may beadministered in a separate formulation which may be administered before,after or simultaneously with the compounds of this invention. Whenadministered in combination with at least one other anti-cancer agentabout 5 to about 100 mg/kg, more preferably about 0.005 to about 10mg/kg, of the present HDAC inhibitors are administered to the patient.Higher and lower dosages may be used. The dosages of the otheranti-cancer agents are known in the art. Administration may occur once aday, or several times in a day. In addition the treatment may berepeated every 7, 14, 21 or 28 days.

The active compound is effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It, willbe understood, however, that the amount of the compound actuallyadministered will be determined by a physician, in the light of therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, it is meant that the activeingredient is dispersed evenly throughout the composition so that thecomposition may be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulation isthen subdivided into unit dosage forms of the type described abovecontaining from, for example, 0.1 to about 500 mg of the activeingredient of the present invention.

The tablets or pills of the present invention may be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permit theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol, and cellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude aqueous solutions suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. Preferably, the compositions are administered by the oral ornasal respiratory route for local or systemic effect. Compositions inpreferably pharmaceutically acceptable solvents may be nebulized by useof inert gases. Nebulized solutions may be breathed directly from thenebulizing device or the nebulizing device may be attached to a facemasks tent, or intermittent positive pressure breathing machine.Solution, suspension, or powder compositions may be administered,preferably orally or nasally, from devices which deliver the formulationin an appropriate manner.

The following formulation examples illustrate the pharmaceuticalcompositions of the present invention.

FORMULATION EXAMPLE 1

Hard gelatin capsules containing the following ingredients are prepared:

Quantity Ingredient (mg/capsule) Active Ingredient 30.0 Starch 305.0Magnesium stearate 5.0

The above ingredients are mixed and filled into hard gelatin capsules in340 mg quantities.

FORMULATION EXAMPLE 2

A tablet formula is prepared using the ingredients below.

Quantity Ingredient (mg/tablet) Active Ingredient 25.0 Cellulose,microcrystalline 200.0 Colloidal silicon dioxide 10.0 Stearic acid 5.0

The components are blended and compressed to form tablets, each weighing240 mg.

FORMULATION EXAMPLE 3

A dry powder inhaler formulation is prepared containing the followingcomponents:

Ingredient Weight % Lactose 5 Active Ingredient 95

The active mixture is mixed with the lactose and the mixture is added toa dry powder inhaling appliance.

FORMULATION EXAMPLE 4

Tablets, each containing 30 mg of active ingredient, are prepared asfollows:

Quantity Ingredient (mg/tablet) Active Ingredient 30.0 mg Starch 45.0 mgMicrocrystalline cellulose 35.0 mg Polyvinylpyrrolidone 4.0 mg (as 10%solution in water) Sodium carboxymethyl starch 4.5 mg Magnesium stearate0.5 mg Talc 1.0 mg Total 120 mg

The active ingredient, starch and cellulose are passed through a No. 20mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinyl-pyrrolidone is mixed with the resultant powders, which arethen passed through a 16 mesh U.S. sieve. The granules so produced aredried at 50° to 60° C. and passed through a 16 mesh U.S. sieve. Thesodium carboxymethyl starch, magnesium stearate, and talc, previouslypassed through a No. 30 mesh U.S. sieve, are then added to the granuleswhich, after mixing, are compressed on a tablet machine to yield tabletseach weighing 150 mg.

FORMULATION EXAMPLE 5

Capsules, each containing 40 mg of medicament are made as follows:

Quantity Ingredient (mg/capsule) Active Ingredient 40.0 mg Starch 109.0mg Magnesium stearate 1.0 mg Total 150.0 mg

The active ingredient, cellulose, starch, an magnesium stearate areblended, passed through a No. 20 mesh U.S. sieve, and filled into hardgelatin capsules in 150 mg quantities.

FORMULATION EXAMPLE 6

Suppositories, each containing 25 mg of active ingredient are made asfollows:

Ingredient Amount Active Ingredient 25 mg Saturated fatty acidglycerides to 2,000 mg

The active ingredient is passed through a No. 60 mesh U.S. sieve andsuspended in the saturated fatty acid glycerides previously melted usingthe minimum heat necessary. The mixture is then poured into asuppository mold of nominal 2.0 g capacity and allowed to cool.

FORMULATION EXAMPLE 7

Suspensions, each containing 50 mg of medicament per 5.0 mL dose aremade as follows:

Ingredient Amount Active Ingredient 50.0 mg Xanthan gum 4.0 mg Sodiumcarboxymethyl cellulose (11%) 50.0 mg Microcrystalline cellulose (89%)Sucrose 1.75 g Sodium benzoate 10.0 mg Flavor and Color q.v. Purifiedwater to 5.0 mL

The medicament, sucrose and xanthan gum are blended, passed through aNo. 10 mesh U.S. sieve, and then mixed with a previously made solutionof the microcrystalline cellulose and sodium carboxymethyl cellulose inwater. The sodium benzoate, flavor, and color are diluted with some ofthe water and added with stirring. Sufficient water is then added toproduce the required volume.

FORMULATION EXAMPLE 8

Quantity Ingredient (mg/capsule) Active Ingredient 15.0 mg Starch 407.0mg Magnesium stearate 3.0 mg Total 425.0 mg

The active ingredient, cellulose, starch, and magnesium stearate areblended, passed through a No. 20 mesh U.S. sieve, and filled into hardgelatin capsules in 560 mg quantities.

FORMULATION EXAMPLE 9

An intravenous formulation may be prepared as follows:

Ingredient Quantity Active Ingredient 250.0 mg Isotonic saline 1000 mL

FORMULATION EXAMPLE 10

A topical formulation may be prepared as follows:

Ingredient Quantity Active Ingredient 1-10 g Emulsifying Wax 30 g LiquidParaffin 20 g White Soft Paraffin to 100 g

The white soft paraffin is heated until molten. The liquid paraffin andemulsifying wax are incorporated and stirred until dissolved. The activeingredient is added and stirring is continued until dispersed. Themixture is then cooled until solid.

Another preferred formulation employed in the methods of the presentinvention employs transdermal delivery devices (“patches”). Suchtransdermal patches may be used to provide continuous or discontinuousinfusion of the compounds of the present invention in controlledamounts. The construction and use of transdermal patches for thedelivery of pharmaceutical agents is well known in the art. See, e.g.,U.S. Pat. No. 5,023,252, issued Jun. 11, 1991, herein incorporated byreference. Such patches may be constructed for continuous, pulsatile, oron demand delivery of pharmaceutical agents.

Direct or indirect placement techniques may be used when it is desirableor necessary to introduce the pharmaceutical composition to the brain.Direct techniques usually involve placement of a drug delivery catheterinto the host's ventricular system to bypass the blood-brain barrier.One such implantable delivery system used for the transport ofbiological factors to specific anatomical regions of the body isdescribed in U.S. Pat. No. 5,011,472 which is herein incorporated byreference.

Indirect techniques, which are generally preferred, usually involveformulating the compositions to provide for drug latentiation by theconversion of hydrophilic drugs into lipid-soluble drugs. Latentiationis generally achieved through blocking of the hydroxy, carbonyl,sulfate, and primary amine groups present on the drug to render the drugmore lipid soluble and amenable to transportation across the blood-brainbarrier. Alternatively, the delivery of hydrophilic drugs may beenhanced by intraarterial infusion of hypertonic solutions which cantransiently open the blood-brain barrier.

Utility

Deacetylases are found in transcriptional repression pathways. Inaddition, histone deacetylases (HDAC) play an important role in cellproliferation and differentiation. Inhibition of histone deacetylationresults in cell cycle arrest, cellular differentiation, apoptosis andreversal of the transformed phenotype. Therefore, HDAC inhibitors areuseful in the treatment and/or amelioration of cell proliferativediseases or conditions, such as cancers.

The following synthetic and biological examples are offered toillustrate this invention and are not to be construed in any way aslimiting the scope of this invention. Unless otherwise stated, alltemperatures are in degrees Celsius.

EXAMPLES

In the examples below, the following abbreviations have the followingmeanings. If an abbreviation is not defined, it has its generallyaccepted meaning.

-   -   Boc=N-tert-butoxycarbonyl    -   d=doublet    -   dd=doublet of doublets    -   DCM=dichloromethane    -   DMEM=Delbaco's minimum eagle's medium    -   DMSO=dimethylsulfoxide    -   DEAD=Diethyl azodicarboxylate    -   DIEA=diisopropylethylamine    -   EtOAc=ethyl acetate    -   g=grams    -   h=hour    -   HOAT=1-hydroxy-7-azabenzotriazole    -   HOBT=1-hydroxybenzotriazole    -   HPLC high performance liquid chromatography    -   hr or h=hour    -   L=liter    -   m=multiplet    -   M=molar    -   Me=methyl    -   min=minutes    -   mg=milligram    -   mL=milliliter    -   mm=millimeter    -   mM=millimolar    -   mmol=millimol    -   MHz=megahertz    -   m/e or m/z=mass to charge ratio from mass spectrum    -   N=normal    -   nm=nanometers    -   NMR=nuclear magnetic resonance    -   PDA=    -   q.s.=means adding a quantity sufficient to achieve a certain        state    -   RPHPLC reverse phase high performance liquid chromatography    -   rt=room temperature    -   Rt=Retention time    -   s=singlet    -   sec=seconds    -   t=triplet    -   TCA=trichloroacetic acid    -   TFA=trifluoroacetic acid    -   THF=tetrahydrofuran    -   TLC or tlc=thin layer chromatography    -   w/v=weight to volume    -   v/v volume to volume    -   μL=microliter    -   μM=micromolar

All the chemicals starting materials were obtained from commercialsuppliers and used without further purification.

Flash column chromatography was performed with silica (60-120 mesh).Analytical RPHPLC was done using Shimadzu HPLC equipped with a PDAdetector using the following columns and systems: a Thermo Hypersil BDS,4.6×150 mmm, 5 μM particle size, C-18 column, isocratic usingacetonitrile:0.1% TFA in water (60:40), flow rate=0.5 mL/min (System-1);Thermo Hypersil BDS, 4.6×250 mm, 5 μM particle size, C-18 column, lineargradient A-acetonitrile: B-0.1% TFA in water; 0.01 min A(10%):B(90%);5.00 min A(10%):B(90%); 15.0 min A(90%):B(10%); 20.00 min A(90%):B(10%);25.00 min A(10%):B(90%); 30.00 min A(10%):B(90%); 30.00 min Stop; flowrate=1.5 mL/min (System-2).

1H NMR spectra were recorded at 200 or 300 MHz and the proton chemicalshifts are expressed in ppm relative to internal tetramethylsilane andcoupling constants (J) are expressed in hertz. Mass spectra were carriedout using a Micromass model.

Method A

To bromothiazole 1 (1 g, 4.18 mmol) in acetonitrile (40 mL) was addedpotassium (1.32 g, 10 mmol) followed by N-Boc piperizine 2a (0.935 g, 5mmol). The reaction mixture was held at 80° C. for 16 h. At the end ofthe reaction time, acetonitrile was removed on roto-evaporation and theresidue was taken in ethyl acetate (50 mL) and washed with brine (30mL). The crude product 3 obtained (1.4 g, 99%) on removal of solvent wastaken as such for the next reaction.

Method B

To the crude product 3 obtained from general method A (1.4 g, 4.15 mmol)TFA (20%) in dichloromethane was added and stirred at room temperaturefor an h. After removing the solvent, the residue was kept under highvacuum for 1 h. The residue was then redissolved in DCM (20 mL) to whichtriethylamine (6.0 mL, 41.5 mmol) and 2-naphthalene sulfonyl chloride(1.85 g, 8.2 mmol) was added and stirred at room temperature over night.Subsequently more DCM (50 mL) was added and washed with 1N hydrochloricacid (20 nit). The crude product obtained on removal of solvent waspurified on a column chromatography using ethyl acetate in hexanes (1:1)to obtain product 4 (1.15 g, %) as white crystalline solid.

Method C

To the product 4 (200 mg, 0.46 mmol) in methanol (5 mL), aqueoushydroxyl amine (30 μL, 4.60 mmol, 50% solution) and sodium hydroxide(118 mg, 3.22 mmol, 2 mL) in water (2 mL) was added and the reactionmixture was held at 0° C. for 4 hours. After acidification with 1N HCl,the solvent was removed and the residue was taken up in ethyl acetateand washed with brine. The product 5 obtained (100 mg) on removal ofsolvent was purified on a RPHPLC.

Method C′

To the product 4 (200 mg, 0.46 mmol) in methanol (5 mL) and dioxane (5mL) was added potassium hydroxide (285 mg) and the mixture was stirredat reflux temperature for 3 hours. The solvent was evaporated, theresidue mixed with water, and the mixture acidified with 2N hydrochloricacid. The mixture was extracted with ethyl acetate, the extracts weredried, and the solvent evaporated to give the carboxylic acid 5d (173mg). To a solution of 5d (100 mg, 0.264 mmol) in dichloromethane (10 mL)were added EDCI.HCl (101.13 mg, 0.52 mmol), HOBT (35.64 mg, 0.26 mmol),DIPEA (68.18 mg, 0.527 mm01) and NH₂OTHP (29.81 mg, 0.264 mmol) under N₂atmosphere. The reaction mixture was stirred at room temperature for 12h progress of the reaction was monitored by TLC analysis). Water (10 mL)followed by dichloromethane (10 ml) were added to the reaction mixtureand the organic layer was separated, dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by column chromatography using silica gel to obtain THPhydroxamate 5e (81 mg). To a solution of 5e (60 mg) in methanol (1 mL)was added 23% v/v HCl in ether (4 mL) at 0° C. The reaction mixture wasstirred at 0° C. temperature for 15 min progress of the reaction wasmonitored by TLC analysis). Solvent was completely removed and to thecrude residue was added diethyl ether and filtered to give 5f as a solid(42 mg).

Example 1 Synthesis of-(2-naphthylsulfonyl)-4-(5-hydroxyaminocarbonylthiazol-2-yl) piperazine

Intermediate 3a was obtained by the general Method A using methyl2-bromothiazole-5-carboxylate 1a and N-Boc piperazine 2a. TLC(Rt): 0.41(30% EtOAc in hexanes).

¹H NMR (300 MHz, CDCl₃) δ 7.76 (s, 1), 3.78 (s, 3), 3.66-3.69 (m, 4),3.19-3.22 (m, 4), 1.49 (s, 9).

MS (ES +): 328 (M+1).

Intermediate 4a was obtained by employing the general Method B using theintermediate 3a. TLC(Rt): 0.41 (30% EtOAc in hexanes).

¹H NMR (300 MHz, CDCl₃): δ8.32 (d, J=1.5 Hz, 1H), 7.89-7.98 (m, 4H),7.76 (s, 1H), 7.70-7.73 (dd, J=1.8, 8.4 Hz, 1H), 7.61-7.66 (m, 2H), 3.78(s, 3H), 3.66-3.69 (m, 4H), 3.19-3.22 (m, 4H).

MS (ES +): 418 (M+1).

The title compound was obtained by employing the general Method C usingthe intermediate 4a. TLC(Rt): 0.41 (30% EtOAc in hexanes).

¹H NMR (300 MHz, CD₃OD) δ: 8.41 (m, 1H), 7.97-8.10 (m, 3H), 7.76-7.80(dd, J=1.8, 8.4 Hz, 1H), 7.76 (s, 1H), 7.64-7.69 (m, 2H), 3.66-3.69 (m,4H), 3.23-3.20 (m, 4H).

MS (ES +): 419 (M+1).

Example 2 Synthesis of1-(2-naphthylsulfonyl)-4-(5-hydroxyaminocarbonylthiazol-2-yl)-1,4-diazepane

Intermediate 3b was obtained by the general Method A using methyl2-bromothiazole-5-carboxylate 1a and N-Boc homopiperazine 2b. Yield(1.56 g, 99%). TLC (Rt): 0.33 (25% EtOAc in hexanes).

¹H NMR (300 MHz, CDCl₃) 6; 7.70 (s, 1), 3.82-3.85 (m, 2H) 3.78 (s, 3H),3.68-3.72 (m, 2H), 3.52-3.56 (m, 21), 3.33-3.37 (m, 2H), 2.09-2.13 (s,2H) 1.49 (s, 9H).

MS (ES +): 342 (M+1).

Intermediate 4b was obtained by employing the general Method B using theintermediate 3b. Yield: 50%. TLC(Rt); 0.33 (50% EtOAc in hexanes).

¹H NMR (300 MHz. CDCl₃) 6; 8.32 (m, 1H), 7.84-7.96 (m, 3H), 7.70 (s,1H), 7.67-7.71 (m, 1H), 7.58-7.62 (m, 2H), 3.82-3.85 (m, 2H) 3.78 (s,3H), 3.68-3.72 (m, 2H), 3.52-3.56 (m, 2H), 3.33-3.37 (m, 2H), 2.09-2.13(s, 2H).

MS (ES +): 432 (M+1).

The title compound was obtained by employing the general Method C usingthe intermediate 4b. TLC(Rt): 0.41 (30% EtOAc in hexanes).

¹H NMR (300 MHz, CD₃OD) δ: 8.35 (m, 1H), 7.90-8.00 (m, 3H), 7.72-7.59(dd, J=1.8, 8.4 Hz, 1H), 7.60-7.64 (m, 2H), 7.52 (s, 1H), 3.74-3.76 (m,2H), 3.66-3.69 (m, 4H), 3.50-3.52 (m, 2H), 1.95-2.00 (m, 2H);

MS (ES +): 433 (M+1).

Example 3 Synthesis of1-(2-naphthylsulfonyl)-4-(4-hydroxyaminocarbonylthiazol-2-yl)piperazine

Intermediate 3c was obtained by the general Method A using methyl2-bromothiazole-4-carboxylate 1a and N-Boc piperazine 2a. Yield (1.4 g,99%). TLC(Rt): 0.37 (20% EtOAc in hexanes).

¹H NMR (300 MHz, CDCl₃) δ: 7.40 (s, 1H), 4.31 (q, J=6.9, 13.8 Hz, 2H),3.62-3.66 (m, 4H), 3.19-3.22 (m, 4H), 1.57 (s, 9H), 1.30 (t, J=7.2 Hz,3H).

MS (ES +): 342 (M+1).

Intermediate 4a was obtained by employing the general Method B using theintermediate 3a. TLC(Rt): 0.41 (30% EtOAc in hexanes).

¹H NMR (300 MHz, CDCl₃) δ: 8.32 (d, J=1.5 Hz, 1H), 7.89-7.98 (m, 3H),7.70-7.74 (dd, J=1.8, 8.4 Hz, 1H), 7.61-7.66 (m, 2H), 7.40 (s, 1H), 4.31(q, J=6.9, 13.8 Hz, 2H), 3.62-3.66 (m, 4H), 3.19-3.22 (m, 4H), 1.57 (s,9H), 1.30 (t, J=7.2 Hz, 3H).

MS (ES +): 432 (M+1).

The title compound was obtained by employing the general Method C usingthe intermediate 4c.

¹H NMR (300 MHz, CD₃OD) δ 8.41 (m, 1H), 7.97-8.10 (m, 3H), 7.56-7.79 (ddJ=1.8, 8.4 Hz, 1H), 7.64-7.69 (m, 2H), 7.37 (s, 1H), 3.61-3.58 (ma, 4H),3.17-3.21 (m, 4H);

MS (ES +): 419 (M+1).

Example 4 Synthesis of1-(2-naphthylsulfonyl)-4-[(5-(2-hydroxyaminocarbonylethen-1(E)-yl-thiazol-2-yl)piperazine

Intermediate 7 was obtained by the general Method A using2-bromo-5-formylthiazole 6 and N-Boc piperazine 2a. Yield: 99%. TLC(Rt):0.31 (50% EtOAc in hexanes).

¹H NMR (300 MHz, CDCl₃) δ: 9.69 (s, 1H), 7.85 (s, 1H), 3.57-3.64 (m,8H), 1.48 (s, 9H).

MS (ES +); 298 (M+1).

Intermediate 8 was obtained by employing the Wittig Horner reaction.Accordingly, to trimethylphosphano acetate (0.23 mL, 1.60 mmol) in THF(10 mL) at −30° C., butyl lithium (0.64 μL, 2.5 M solution in THF) wasadded and stirred at −30° C. for an hour. Intermediate 7 (0.4 g, 1.35mmol) in THF (5 mL) was then added and stirred for another 2 hours whilethe temperature was brought to 0° C. After quenching the reaction withsaturated aqueous ammonium chloride solution (20 mL), the product wasextracted with ethyl acetate. The residue obtained on removal of solventwas purified on silica gel column chromatography using 30% ethyl acetatein hexanes (0.4 g, 84%). TLC(Rt): 0.57 (33% EtOAc in hexanes).

¹H NMR (300 MHz, CDCl₃) δ: 7.68 (d, J=15.9 Hz, 1H), 7.34 (s, 1H), 5.80(d, J=15.3 Hz, 1H), 3.75 (s, 3H), 3.55 (m, 8H), 1.48 (s, 9H).

MS (ES +): 354 (M+1).

Intermediate 9 was obtained by employing the general Method B using theintermediate 8. Yield: 0.3 g, 40%). TLC(Rt): 0.52 (50% EtOAc inhexanes).

¹H NMR (300 MHz, CDCl₃) δ: 8.32 (d, J=1.5 Hz, 1H), 7.89-7.98 (m, 3H),7.70-7.73 (dd, J=1.8, 8.4 Hz, 1H), 7.61-7.66 (m, 3H), 7.61 (s, 1H), 5.70(d, J=15.3 Hz, 1H), 3.73 (s, 3H), 3.66-3.69 (m, 4H), 3.19-3.22 (m, 4H).

MS (ES +): 444 (M+1).

The title compound was obtained by employing the general Method C usingthe intermediate 9.

¹H NMR (300 MHz, DMSO-d₆) δ: 10.51 (s, 1H), 8.92 (s, 1H), 8.44 (s, 1H),8.05-8.21 (m, 3H), 7.67-7.76 (m, 3H), 7.39 (s, 1H), 5.70 (d, J=15.3 Hz,1H), 3.59 (m, 4), 3.10 (m, 4H).

MS (ES +): 445 (M+1).

Following the procedures set forth in Example 4 above, except thatMethod C′ rather than Method C was used for the hydroxamic acidformation, the compounds of Examples 4b-4m were prepared using theappropriate starting materials and the ¹H NMR data, HPLC and/or massspectral data are presented below.

Example 4b1-(phenylsulfonyl)-4-[(5-(2-hydroxyaminocarbonylethen-1(E)-yl-thiazol-2-yl)piperazine

A solid (42 mg); HPLC (RT=13.09 min); ¹H NMR (200 MHz, CD₃OD) δ;3.26-3.34 (m, 4H), 3.78-3.83 (m, 4H), 6.03-6.1 (d, 1H, J=15.4 Hz),7.54-7.92 (m, 7H).

Example 4c1-(3,4-dimethoxyphenylsulfonyl)-4-[(5-(2-hydroxyaminocarbonylethen-1(E)-yl-thiazol-2-yl)piperazine

A solid (30 mg); HPLC (RT=12.88 nm); ¹H NMR (200 MHz, CD-OD) δ:3.23-4H), 3.79-3.81 (m, 4H), 3.925 (s, 6H), 5.99-6.07 (d, 1H, J=15.2Hz), 7.15-7.62 (m,

Example 4d1-(4-methoxyphenylsulfonyl)-4-[(5-(2-hydroxyaminocarbonylethen-1(E)-yl-thiazol-2-yl)piperazine

A solid (30 mg); HPLC (RT=13.26 min); ¹H NMR (200 MHz, CD₃OD) δ:3.25-3.31 (m, 4H), 3.8 (m, 4H), 3.9 (s, 3H), 6.03-6.1 (d, 1H, J=15.4Hz), 7.13-7.18 (d, 2H, J=8.8 Hz), 7.62-7.65 (m, 1H), 7.76-7.8 (d, 2H,J=8.8 Hz), 7.92 (s, 1H).

Example 4e1-(4-trifluoromethoxyphenylsulfonyl)-4-[(5-(2-hydroxyaminocarbonylethen-1(E)-yl-thiazol-2-yl)piperazine

A solid (38 mg); HPLC (RT=14.61 min); ¹H NMR (200 MHz, CD₃OD) δ:3.31-3.34 (m, 4H), 3.8 (m, 4H), 5.99-6.07 (d, 1H, J=15.4 Hz), 7.55-7.62(m, 3H), 7.92-7.99 (m, 3H).

Example 4f1-(4-methylphenylsulfonyl)-4-[(5-(2-hydroxyaminocarbonylethen-1(E)-yl-thiazol-2-yl)piperazine

A solid (25 mg); HPLC (RT=13.6 min); ¹H NMR (200 MHz, CD₃OD) δ: 2.46 (s,3H), 3.24-3.31 (m, 4H), 3.78-3.8 (m, 4H), 6.03-6.11 (d, 1H, J=15.4 Hz),7.45-7.74 (m, 6H).

Example 4g1-(4-trifluoromethylphenylsulfonyl)-4-[(5-(2-hydroxyaminocarbonylethen1(E)-yl-thiazol-2-yl)piperazine

A solid (45 mg); HPLC (RT=14.49 min); ¹H NMR (200 MHz, CD₃OD) δ:3.31-3.36 (m, 4H), 3.83 (m, 4H), 6.04-6.12 (d, 1H, J=15.4 Hz), 7.13-7.18(d, 2H, J=8.8 Hz), 7.54-7.66 (m, 2H), 7.96-8.08 (m, 4H).

Example 4h1-(4-nitrophenylsulfonyl-4-[(5-(2-hydroxyaminocarbonylethen-1(E)-yl-thiazol-2-yl)piperazine

A solid (45 mg); HPLC (RT=13.47 min); ¹H NMR (200 MHz, CD₃OD) δ: 3.33(m, 4H), 3.84 (m, 4H), 6.02-6.09 (d, 1H, J=15.4 Hz), 7.54-7.65 (m, 2H),8.08-8.12 (d, 2H, J=8.8 Hz), 8.47-8.51 (d, 2H, J=8.8 Hz).

Example 4i1-(thien-2-ylsulfonyl-4-[(5-(2-hydroxyaminocarbonylethen-1(E)-yl-thiazol-2-yl)piperazine

A solid (45 mg); HPLC (RT=12.99 min); ¹H NMR (200 MHz, CD₃OD) 6;3.27-3.36 (m, 4H), 3.79-3.84 (m, 4H), 5.99-6.07 (d, 1H, J=15.8 Hz),7.25-7.30 (m, 1H), 7.55-7.70 (m, 3H), 7.91-7.94 (d, 1H, J=6.2 Hz).

Example 4j1-(1,1′biphenylsulfonyl-4-[(5-(2-hydroxyaminocarbonylethen-1(E)-yl-thiazol-2-yl)piperazine

A solid (45 mg); HPLC (RT=14.91 min); ¹H NMR (200 MHz, CD₃OD) δ:3.31-3.36 (m, 4H), 3.79-3.82 (m, 4H), 6.0-6.08 (d, 1H, J=15.4 Hz),7.44-7.73 (m, 7H), 7.92 (m, 4H).

Example 4k1-(5-dimethylamino-naphthalene-1-sulfonyl)-4-[(5-(2-hydroxyaminocarbonlethen-1(E)-yl-thiazol-2-yl)piperazine

A solid (35 mg); HPLC (RT=13.41 min); ¹H NMR (200 MHz, CD₃OD) δ: 3.33(m, 4H), 3.47 (s, 6H), 3.75 (m, 4H), 6.06 (d, 1H, J=15.4 Hz), 7.57 (m,2H), 7.92-8.0 (m, 2H), 8.09-8.13 (d, 1H, J=7.6 Hz), 8.44-8.48 (d, 1H,J=7 Hz), 8.63-8.68 (d, 1H, J=8.4 Hz), 8.92-8.97 (d, 1H, J=8.8 Hz).

Example 4m1-(4-fluorophenylsulfonyl)-4-[(5-(2-hydroxyaminocarbonylethen-1(E)-yl-thiazol-2-yl)piperazine

A solid (15 mg); HPLC (RT=13.30 min); ¹H NMR (200 MHz, CD₃OD) δ 3.33 (m,4H), 3.81 (m, 4H), 6.02-6.09 (d, 1H, J=15.4 Hz), 7.36-7.44 (m, 2H), 7.64(m, 2H), 7.92 (m, 2H).

Example 5 Synthesis of4-(2-naphthylsulfonylamino)-1-[(5-(2-hydroxyaminocarbonyl-thiazol-2-yl)-piperadine(20)

Intermediate 18 was obtained by the general Method A using methyl2-bromothiazole-5-carboxylate 1 and 4-N-Boc-aminopiperidine 17. TLC(Rt): 0.28 (25% EtOAc in hexanes).

¹H NMR (300 MHz, CDCl₃) δ 7.79 (s, 1H), 4.63 (d, J=7.8 Hz, 1H),3.86-3.91 (m, 2H), 3.50 (m, 1H), 3.07-3.17 (m, 2H), 1.88-1.93 (m, 1H),1.47-1.60 (m, 2H), 1.49 (s, 9H).

MS (ES +): 342 (M+1).

Intermediate 19 was obtained by employing the general Method B using theintermediate 18. TLC (Rt): 0.41 (30% EtOAc in hexanes).

¹H NMR (300 MHz, CDCl₃) δ: 8.45 (d, J=1.5 Hz, 1H), 7.89-7.98 (m, 3H),7.80-7.84 (dd, J=1.8, 8.4 Hz, 1H), 7.79 (s, 1H), 7.61-7.66 (m, 2H), 4.63(d, J=7.8 Hz, 1H), 3.86-3.91 (m, 2H), 3.50 (m, 1H), 3.07-3.17 (m, 2H),1.88-1.93 (m, 1H), 1.47-1.60 (m, 2H), 1.49 (s, 9H).

MS (ES +); 432 (M+1).

The title compound 20 was obtained by employing the general Method Cusing the intermediate 19.

¹H NMR (300 MHz, CDCl₃) δ: 8.45 (d, J=1.5 Hz, 1H), 7.96-8.07 (m, 3H),7.85-7.89 (dd, J=1.8, 8.4 Hz, 1H), 7.74 (s, 1H), 7.61-7.68 (m, 2H),3.81-3.86 (m, 2H), 3.50 (m, 1H), 3.17-3.27 (m, 2H), 1.88-1.93 (m, 2H),1.47-1.60 (m, 2H).

MS (ES +): 433 (M+1).

Following the procedures set forth in Example 5 above, except thatMethod C′ rather than Method C was used for the hydroxamic acidformation, the compounds of Examples 5b-5d were prepared using theappropriate starting materials and the ¹H NMR data, HPLC and/or massspectral data are presented below.

Example 5b4-(1,1′-biphenylsulfonylamino)-1-[(5-(2-hydroxyaminocarbonyl-thiazol-2-yl)-piperadine

A white solid (50 mg); HPLC (RT=14.26 min); ¹H NMR (CD₃OD, 200 MHz) δ:7.91 (4H, s), 7.74-7.44 (6H, m), 3.87-3.52 (3H, m), 2.76 (2H, m), 2.13(2H, m), 1.78 (2H, m); MS (m/z) 455 (M+H⁺).

Example 5c4-(3,4-dimethoxyphenylsulfonylamino)-1-[(5-(2-hydroxyaminocarbonyl-thiazol-2-yl)-piperadine

A white solid (49 mg); HPLC (RT=12.12 min); ¹H NMR (CD₃OD, 200 MHz) δ:7.45 (1H, dd, J=2.2, 8.4 Hz), 7.29 (1H, d, J=2.2 Hz), 7.12 (1H, d, J=8.4Hz), 3.94 (3H, s), 3.87 (3H, s), 3.75-3.57 (3H, m), 2.70 (2H, m), 2.17(2H, m), 1.75 (2H, m); MS (m/z) 442 (M+H3.

Example 5d4-(4-methylphenylsulfonylamino)-1-[(5-(2-hydroxyaminocarbonyl-thiazol-2-yl)-piperadine

A white solid (50 mg); HPLC (RT=12.86 min); ¹H NMR (CD₃OD, 200 MHz) δ:7.77 (2H, d, J=8.4 Hz), 7.50 (2H, d, J=8.4 Hz), 3.80-3.48 (3H, m), 2.64(2H, m), 2.52 (3H, s), 2.17 (2H, m), 1.75 (2H, m); MS (m/z) 396 (M+H⁺).

Example 5e2-(4-{[(1,1′-biphenylsulfonyl)amino]methyl}piperidin-1-yl)-1,3-thiazole-5-carboxylicacid hydroxyamide

Intermediate 7B.2 was obtained by the general Method A using methyl2-bromothiazole-5-carboxylate 1 and 4-aminomethylpiperidine 7B.1. ¹HNMR200 MHz (CDCl₃) δ: 1.25-1.4 (m, 4H), 1.53-1.59 (m, 1H), 1.84-1.89 (d,2H, J=11.8 Hz), 2.65-2.65 (d, 2H, J=6.6 Hz), 3.02-3.16 (t, 3H), 3.82 (s,3H), 4.06-4.13 (d, 2H, J=12.4 Hz), 7.86 (s, 1H).

Intermediate 7B.3 was obtained by employing the general Method B usingthe intermediate 7B.2. ¹HNMR 200 MHz (CDCl₃) 6; 1.25-1.36 (m, 3H), 1.60(m, 2H), 1.82-1.886 (m, 2H), 2.88-2.989 (m, 2H), 3.81 (s, 3H),4.037-4.10 (m, 2H), 4.67 (t, 1H), 7.26-7.94 (m, 10H).

The title compound 7B.4 (Example 5e) was obtained by employing thegeneral Method C′ using the intermediate 7B.3.

A white solid (75 mg); HPLC (RT=14.56 min); ¹H NMR 200 MHz (CD₃OD) δ:1.3-1.47 (m, 1H), 1.95-2.02 (m, 4H), 2.85-2.88 (d, 2H, J=6.4 Hz),3.31-3.48 (m, 2H), 3.95-4.01 (d, 2H, J=12.8 Hz), 7.43-7.96 (m, 10H)

Example 5f2-{[1-(2-naphthalsulfonyl)piperidin-4-yl]amino}-1,3-thiazole-5-carboxylicacid hydroxyamide

Intermediate 7C.2 was obtained by the general Method A using methyl2-bromothiazole-5-carboxylate 1 and 1-N-Boc-4-aminopiperidine 7C.1. HPLC90.47% (RT 6.66 min); ¹H NMR 200 MHz (CDCl₃) δ: 7.81 (1H, s), 6.13 (1H,bs), 4.11 (2H, m), 3.83 (3H, s), 3.46 (1H, m), 2.93 (2H, m), 2.14 (2H,m), 1.47 (11H, m).

Intermediate 7C.3 was obtained by employing the general Method B usingthe intermediate 7C.2. A white solid (170 mg); HPLC (RT=10.88 min); ¹HNMR (CDCl₃, 200 MHz) 6; 8.35 (1H, s), 8.02-7.93 (3H, m), 7.78-7.63 (4H,m), 5.62 (1H, d, J=7.2 Hz), 3.79 (3H, s), 3.76 (2H, m), 3.42 (1H, m),2.62 (2H, m), 2.18 (2H, m), 1.63 (2H, m).

The title compound 7C.4 (Example 5f) was obtained by employing thegeneral Method C′ using the intermediate 7C.3. A white solid (40 mg);HPLC (RT=13.55 min); MS (m/z) 438 (M+H⁺),

Example 5g2-(6-{[(4-methylphenyl)sulfonyl]amino}-3-azabicyclo[3.1.0]hex-3-yl)-1,3-thiazole-5-carboxylicacid hydroxyamide

Intermediate 7D.2 was obtained by the general Method A using methyl2-bromothiazole-5-carboxylate 1 and 3-azabicyclo[3.1.0]hexan-6-amine7D.1. MS m/e: 240 (M+H⁺).

Intermediate 7D.3 was obtained by employing the general Method B usingthe intermediate 7D.2. ¹HNMR (200 MHz, CD₃OD) δ: 7.79 (s, 1H), 7.71 (d,2H, J=8.0 Hz), 7.35 (d, 2H, J=8.0 Hz), 3.81 (s, 3H), 3.57 (m, 5H), 2.44(s, 3H), 2.095 (m, 2H); MS m/e=394 (M+H⁺).

The title compound 7D.4 (Example 5g) was obtained by employing thegeneral Method C′ using the intermediate 7D.3. A white solid (44 mg); ¹HNMR (CD₃OD, 200 MHz) 6; 7.95 (s, 1H), 7.81 (d, 2H, J=8.2 Hz), 7.46 (d,2H, J=8.2 Hz); 3.95-3.61 (m, 5H), 2.44 (s, 3H), 2.16 (m, 2H); MS m/e=395(M+H⁺); HPLC (RT: 12.14 min).

Example 5h2-[3-[(4-methylphenyl)sulfonyl]tetrahydropyrimidin-1(2H)-yl]-1,3-thiazole-5-carboxylicacid hydroxylamide

To a solution of tert-butyl 5,6-dihydropyrimidine-1(4H)-carboxylate 7E.1(350 mg, 1190 mmole) in methanol (10 mL) was added potassium borohydride(205 mg, 3.80 mmoles) at 0° C. The reaction mixture was stirred at roomtemperature for 2 hours. After completion of the reaction, ice (10 g)was added to the mixture and stirred for 10 min. Solvent was evaporatedunder reduced pressure and the compound was extracted twice withdichloromethane (5 ml). The organic layer was separated, dried oversodium sulfate, filtered and the solvent was removed under reducedpressure to give crude residue, which was purified by columnchromatography using silica gel to provide compound 7E.2 (350 mg, 94%);¹HNMR (CDCl₃) δ: 4.31 (s, 2H), 3.54 (t, 2H, J=5.4 Hz), 2.94 (t, 2H,J=5.4 Hz), 1.54 (m, 2H), 1.46 (s, 9H); MS m/c=186 (M+H⁺).

Intermediate 7E.3 was obtained by the general Method A using methyl2-bromothiazole-5-carboxylate 1 and 7E.2. ¹HNMR (CDCl₃) δ: 7.83 (s, 1H),5.05 (s, 2H), 4.27 (q, 2H, J=5.0, 7.2 Hz), 3.72 (t, 211, J=5.4 Hz), 3.59(t, 2H, J=5.4 Hz), 1.77 (m, 2H), 1.48 (s, 9H), 1.38 (t, 3H, J=7.2 Hz);MS m/e=342(M+H⁺).

Intermediate 7E.4 was obtained by employing the general Method B usingthe intermediate 7E.3. ¹H NMR (CDCl₃+DMSO-D₆, 200 MHz) δ: 7.85 (s, 1H),5.08 (s, 2H), 4.31 (q, 2H, J=5.1, 7.2 Hz), 3.75 (t, 2H, J=5.2 Hz), 3.44(t, 2H, J=5.2 Hz), 2.09 (m, 2H), 1.37 (t, 3H, J=7.2 Hz); MS m/e=242(M+H⁺).

The title compound 7E.5 (Example 5h) was obtained by employing thegeneral Method C′ using the intermediate 7E.4. A solid (36 mg, 68%yield); ¹H NMR (CD₃OD, 200 MHz) δ: 7.91 (bs, 1H), 7.73 (d, 2H, J=8.6Hz), 7.39 (d, 2H, J=8.6 Hz); 5.12 (s, 2H), 3.64-3.54 (m, 4H), 2.43 (s,3H), 1.76 (m, 2H); MS m/e=383 (M+1); HPLC (RT: 12.89 min).

Example 6

Preparation of 2-piperazin-1-yl-thiazole-5-carboxylic acid methyl ester(11)

To a solution of methyl 2-bromothiazole-5-carboxylate (1a) (5.00 g,22.50 mmol) in acetonitrile (50 mL) were added piperazine 2 (2.32 g,26.97 mmol) and potassium carbonate (6.22 g, 45.05 mmol) under a N₂atmosphere. The reaction mixture was heated to reflux at 80° C. for 10h. The reaction mixture was filtered through Celite and the filtrate wasconcentrated under reduced pressure. The residue was purified by columnchromatography using silica gel to give the compound II as a solid (4.10g, 79.8%). HPLC: 92% (Rt=3.883 min).

¹H NMR (CDCl₃, 200 MHz) δ: 7.88 (1H, s), 3.89 (3H, s), 3.55 (4H, t J=6.0Hz), 2.98 (4H, t, J=6.0 Hz).

MS (m/z): 228 (M+1).

Preparation of 2-[4-(3,4-dimethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic acid methyl ester (12b)

To a solution of intermediate 11 (200 mg, 0.886 mmol) in dichloromethane(7.5 mL) were added 3,4-dimethoxybenzenesulfonyl chloride (320 mg, 1.320mmol) and triethylamine (220 mg, 2.169 mmol) under a N₂ atmosphere. Thereaction mixture was stirred at room temperature for 4 h. Water (10 mL)followed by dichloromethane (10 mL) were added to the reaction mixtureand the organic layer was separated, dried on sodium sulfate, filteredand concentrated under reduced pressure. The residue was purified bycolumn chromatography using silica gel to give the compound 12b as asolid (200 mg, 53.0%). HPLC: 99% (Rt=6.507 min).

¹H NMR (CDCl₃, 200 MHz) δ: 7.82 (1H, s), 7.38 (1H, dd, J=2.2, 8.6 Hz),7.19 (1H, d, J=2.2 Hz), 6.96 (1H, d, J=8.6 Hz), 3.93 (6H, 2s), 3.83 (3H,s), 3.68 (4H, t, J=5.2 Hz), 3.14 (4H, t, J=5.2 Hz).

MS (m/z): 427 (M+1).

Preparation of 2-[4-(3,4-dimethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic acid hydroxyamide (13b)

To a solution of compound (12b) (125 mg, 0.292 mmol) in 1,4-dioxane (2mL) were added hydroxylamine hydrochloride (202 mg, 2.92 mmol) and afreshly prepared solution of sodium methoxide in methanol (100 mg, 4.35mmol of sodium dissolved in 1 mL of methanol) under N₂ atmosphere. Thereaction mixture was stirred at room temperature for 2 h. The reactionmixture was acidified to pH˜6 with 1M HCl and the formed precipitateswere filtered off. The filtrate was diluted with ethylacetate (5 mL) andwater (2 mL) and the organic layer was separated. The aqueous layer waswashed with ethyl acetate (5 mL) and the combined organic layers weredried on sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by preparative HPLC to give 13b as asolid. HPLC: 86.09% (Rt=12.51 min).

¹H NMR (CD₃OD, 200 MHz) δ: 8.14 (1H, s), 7.61-7.08 (3H, m), 3.83 (6H,s), 3.54 (4H, m), 3.03 (4H, m).

MS (ES+): 429 (M+1).

Example 7

Preparation of 2-[4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic acid methyl ester (12d)

To a solution of compound II (200 mg, 0.886 mmol) in dichloromethane(7.5 mL) were added 4-trifluoromethoxybenzenesulfonyl chloride (344 mg,1.320 mmol) and triethylamine (220 mg, 2.169 mmol) under a N₂atmosphere. The reaction mixture was stirred at room temperature for 4h. Water (10 mL) followed by dichloromethane (10 mL) were added to thereaction mixture and the organic layer was separated, dried on sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by column chromatography using silica gel to give thecompound 12d as a solid (313 mg, 78.8%). HPLC: 98% (Rt=12.22 min).

¹H NMR (CDCl₃, 200 MHz) δ: 7.82 (3H, m), 7.44 (2H, d, J=8.0 Hz), 3.84(3H, s), 3.74 (4H, t, J=5.8 Hz), 3.20 (4H, t, J=5.8 Hz).

MS (m/z): 451 (M+1).

Preparation of 2-[4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic acid hydroxyamide (13d)

To a solution of compound (12d) (125 mg, 0.276 mmol) in 1,4-dioxane (2mL) were added hydroxylamine hydrochloride (191 mg, 2.76 mmol) and afreshly prepared solution of sodium methoxide in methanol (95 mg, 4.14mmol of sodium dissolved in 1 mL of methanol) under a N₂ atmosphere. Thereaction mixture was stirred at room temperature for 2 h. The reactionmixture was acidified to pH 6 with 1M HCl and the formed precipitateswere filtered off. The filtrate was diluted with ethyl acetate (5 mL)and water (2 mL) and the organic layer was separated. The aqueous layerwas washed with ethyl acetate (5 mL) and the combined organic layerswere dried on sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by preparative HPLC to give 13d as asolid. HPLC: 92% (Rt=14.16 min).

¹H NMR (CD₃OD, 200 MHz) δ: 8.00 (3H, m), 7.57 (2H, m), 3.64 (4H, m),3.19 (4H, m);

MS (m/z): 453 (M+1).

Example 8

Preparation of2-[4-(toluene-4-sulfonyl)-piperazin-1-yl]-thiazole-5-carboxlic acidmethyl ester (12e)

To a solution of compound II (200 mg, 0.886 mmol) in dichloromethane(7.5 mL) were added 4-methyl benzenesulfonyl chloride (251 mg, 1.320mmol) and triethylamine (220 mg, 2.169 mmol) under a N₂ atmosphere. Thereaction mixture was stirred at room temperature for 4 h. Water (10 mL)followed by dichloromethane (10 mL) were added to the reaction mixtureand the organic layer was separated, dried on sodium sulfate, filteredand concentrated under reduced pressure. The residue was purified bycolumn chromatography using silica gel to give the compound 12e as asolid (275 mg, 82%). HPLC: 99.62% (Rt=9.22 min).

¹H NMR (CDCl₃, 200 MHz) δ 7.82 (1H, s), 7.66 (2H, d, J=8.4 Hz), 7.35(2H, d, J=8.4 Hz), 3.82 (3H, s), 3.68 (4H, t, J=5.6 Hz), 3.14 (4H, t,J=5.6 Hz), 2.44 (3H, s).

MS (m/z): 382 (M+1).

Preparation of 2-[4-(4toluene-4-sulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic acidhydroxyamide (13e)

To a solution of compound 12e (125 mg, 0.327 mmol) in 1,4-dioxane (2 mL)were added hydroxylamine hydrochloride (227 mg, 3.27 mmol) and a freshlyprepared solution of sodium methoxide in methanol (112 mg, 4.91 mmol ofsodium dissolved in 1 mL of methanol) under a N₂ atmosphere. Thereaction mixture was stirred at room temperature for 2 h. The reactionmixture was acidified to pH˜6 with 1M HCl and the formed precipitateswere filtered off. The filtrate was diluted with ethyl acetate (5 mL)and water (2 mL) and the organic layer was separated. The aqueous layerwas washed with ethyl acetate (5 mL) and the combined organic layerswere dried on sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by preparative HPLC to give 13e as asolid. HPLC: 90% (Rt=13.23 min).

¹H NMR (CD₃OD, 200 MHz) δ: 7.79 (3H, m), 7.44 (2H, d, J=8.6 Hz), 3.65(4H, t, J=5.4 Hz), 3.12 (4H, t, J=5.4 Hz), 2.46 (3H, s).

MS (m/z): 382.6 (M+1).

Example 9

Preparation of2-[4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylicacid methyl ester (12f)

To a solution of compound 11 (200 mg, 0.886 mmol) in dichloromethane(7.5 mL) were added 4-trifluoromethyl benzenesulfonyl chloride (322 mg,1.320 mmol) and triethylamine (220 mg, 2.169 mmol) under a N₂atmosphere. The reaction mixture was stirred at room temperature for 4h. Water (10 mL) followed by dichloromethane (10 ml) were added to thereaction mixture and the organic layer was separated, dried on sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by column chromatography using silica gel to give thecompound 12f as a solid (333 mg, 86.9%). HPLC: 99.42% (Rt=11.936 min).

¹H HNMR (CDCl₃ 200 MHz) δ: 7.88-7.82 (5H, m), 3.81 (3H, s), 3.70 (4H, t,J=5.2 Hz), 3.19 (4H, t, J=5.2 Hz).

MS (m/z): 435 (M+1), 245.

Preparation of2-[4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylicacid hydroxyamide (13f)

To a solution of compound 12f (125 mg, 0.287 mmol) in 1,4-dioxane (2 mL)were added hydroxylamine hydrochloride (199 mg, 2.87 mmol) and a freshlyprepared solution of sodium methoxide in methanol (99 mg, 4.30 mmol ofsodium dissolved in 1 mL of methanol) under a N₂ atmosphere. Thereaction mixture was stirred at room temperature for 2 h. The reactionmixture was acidified to pH˜6 with 1M ECl and the formed precipitateswere filtered off. The filtrate was diluted with ethyl acetate (5 mL)and water (2 mL) and the organic layer was separated. The aqueous layerwas washed with ethyl acetate (5 mL) and the combined organic layerswere dried on sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by preparative HPLC to give 13f (20mg, yield 16%). HPLC 85.42% (Rt=14.11 min).

¹H NMR (CD₃OD, 200 MHz): δ 8.03 (4H, m), 7.81 (1H, s), 3.75 (4H, m),3.21 (4H, m).

MS (m/z): 436 (M+1).

Example 10

Preparation of2-[4-(4-nitro-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylicacid methyl ester (12g)

To a solution of compound 11 (200 mg, 0.886 mmol) in dichloromethane(7.5 mL) were added 4-nitro benzenesulfonyl chloride (292 mg, 1.320mmol) and triethylamine (220 mg, 2.169 mmol) under a N₂ atmosphere. Thereaction mixture was stirred at room temperature for 4 h. Water (10 mL)followed by dichloromethane (10 mL) were added to the reaction mixtureand the organic layer was separated, dried on sodium sulfate, filteredand concentrated under reduced pressure. The residue was purified bycolumn chromatography using silica gel to give the compound 12g as asolid (120 mg, 33.3%). HPLC: 97% (Rt=7.76 min).

¹H NMR (CDCl₃ DMSO-D₆, 200 MHz) δ: 8.50 (2H, d, J=8.0 Hz), 8.01 (2H, d,J=8.0 Hz), 7.84 (1H, s), 3.81 (3H, s), 3.71 (4H, t, J=5.6 Hz), 3.23 (4H,t, J=5.6 Hz).

Preparation of2-[4-(4-nitro-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylicacid hydroxyamide (13g)

To a solution of compound 12g (125 mg, 0.303 mmol) in 1,4-dioxane (2 mL)were added hydroxylamine hydrochloride (210 mg, 3.03 mmol) and a freshlyprepared solution of sodium methoxide in methanol (104 mg, 4.50 mmol ofsodium dissolved in 1 mL of methanol) under N2 atmosphere. The reactionmixture was stirred at room temperature for 2 h. The reaction mixturewas acidified to pH 6 with 1M HCl and the formed precipitates werefiltered off. The filtrate was diluted with ethyl acetate (5 mL) andwater (2 mL) and the organic layer was separated. The aqueous layer waswashed with ethyl acetate (5 mL) and the combined organic layers weredried on sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by preparative HPLC to give 13g

Example 11

Preparation of2-[4-(4-actyl-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylicacid methyl ester (12h)

To a solution of compound II (200 mg, 0.886 mmol) in dichloromethane(7.5 mL) were added 4-acetyl-benzenesulfonyl chloride (288 mg, 1.320mmol) and triethylamine (220 mg, 2.169 mmol) under a N₂ atmosphere. Thereaction mixture was stirred at room temperature for 4 h. Water (10 mL)followed by dichloromethane (10 mL) were added to the reaction mixtureand the organic layer was separated, dried on sodium sulfate, filteredand concentrated under reduced pressure. The residue was purified bycolumn chromatography using silica gel to give the compound 12h as asolid (346 mg, 96.2%). HPLC: 99.72% (Rt=6.56 min).

¹H NMR (CDCl₃, DMSO-D₆, 200 MHz) δ: 8.10 (2H, d, J=8.0 Hz), 7.89 (2H, d,J=8.0 Hz), 7.79 (1H, s), 3.80 (3H, s), 3.69 (4H, t, J=5.4 Hz), 3.18 (4H,t, J=5.4 Hz), 2.66 (3H, s).

MS (m/z): 410 (M+1).

Preparation of2-[4-(4-acetyl-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylicacid hydroxyamide (13h)

To a solution of compound (12h) (125 mg, 0.305 mmol) in 1,4-dioxane (2mL) were added hydroxylamine hydrochloride (211 mg, 3.05 mmol) and afreshly prepared solution of sodium methoxide in methanol (105 mg, 4.57mmol of sodium dissolved in 1 mL of methanol) under a N₂ atmosphere. Thereaction mixture was stirred at room temperature for 2 h. The reactionmixture was acidified to pH˜6 with 1M HCl and the formed precipitateswere filtered off. The filtrate was diluted with ethyl acetate (5 mL)and water (2 mL) and the organic layer was separated. The aqueous layerwas washed with ethyl acetate (5 mL) and the combined organic layerswere dried on sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by preparative HPLC to give 13h (15mg, yield 12.0%). HPLC: 92.26% (Rt=12.51 min).

¹H NMR (CD₃OD, 200 MHz): δ 7.86-7.68 (5H, m), 3.64 (4H, m), 3.17 (4H,m), 2.26 (3H, s).

Example 12

Preparation of2-[4-(thiophene-2-sulfonyl)-piperazin-1-yl]-thiazole-5-carboxlic acidmethyl ester (12i)

To a solution of compound II (200 mg, 0.886 mmol) in dichloromethane(7.5 mL) were added 2-thiophene sulfonyl chloride (241 mg, 1.320 mmol)and triethylamine (220 mg, 2.169 mmol) under a N7 atmosphere. Thereaction mixture was stirred at room temperature for 4 h. Water (10 mL)followed by dichloromethane (10 mL) were added to the reaction mixtureand the organic layer was separated, dried on sodium sulphate, filteredand concentrated under reduced pressure. The residue was purified bycolumn chromatography using silica gel to give the compound 12i as asolid (300 mg, 91.4%). HPLC: 99.74% (Rt=7.22 min).

¹H NMR (CDCl₃, 200 MHz) δ: 7.83 (1H, s), 7.67-7.55 (2H, m), 7.16 (1H,m), 3.82 (3H, s), 3.71 (4H, t, J=5.4 Hz), 3.20 (4H, t, J=5.4 Hz).

MS (m/z): 373 (M+1).

Preparation of2-[4-(thiophene-2-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylicacid hydroxyamide (13i)

To a solution of compound 12i (125 mg, 0.334 mmol) in 1,4-dioxane (2 mL)were added hydroxylamine hydrochloride (232 mg, 3.34 mmol) and a freshlyprepared solution of sodium methoxide in methanol (115 mg, 5.10 mmol ofsodium dissolved in 1 mL of methanol) under a N₂ atmosphere. Thereaction mixture was stirred at room temperature for 2 h. The reactionmixture was acidified to pH 6 with 1M HCl and the formed precipitateswere filtered off. The filtrate was diluted with ethyl acetate (5 mL)and water (2 mL) and the organic layer was separated. The aqueous layerwas washed with ethyl acetate (5 mL) and the combined organic layerswere dried on sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by preparative HPLC to give 13i (14mg, yield 11.2%). HPLC: 58.9% (Rt=12.55 min).

¹H NMR (CD₃OD, 200 MHz) δ: 8.67 (1H, m), 7.85 (1H, m), 7.78 (1H, s),7.59 (1H, m), 7.20 (1H, m), 3.67 (4H, m), 3.17 (4H, m).

Example 13

Preparation of2-[4-(biphenyl-4-sulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic acidmethyl ester (12j)

To a solution of compound II (200 mg, 0.886 mmol) in dichloromethane(7.5 mL) were added 4-biphenyl sulfonyl chloride (333 mg, 1.320 mmol)and triethylamine (220 mg, 2.169 mmol) under a N₂ atmosphere. Thereaction mixture was stirred at room temperature for 4 h. Water (10 mL)followed by dichloromethane (10 mL) were added to the reaction mixtureand the organic layer was separated, dried on sodium sulfate, filteredand concentrated under reduced pressure. The residue was purified bycolumn chromatography using silica gel to give the compound 12j as asolid (200 mg, 51.2%). HPLC; 99.88% (Rt=15.46 min).

¹H NMR (CDCl₃, 200 MHz) δ: 7.89-7.76 (5H, m), 7.64-7.47 (5H, m), 3.82(3H, s), 3.72 (4H, t, J=5.1 Hz), 3.22 (4H, t, J=5.1 Hz).

Preparation of2-[4-(biphenyl-4-sulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic acidhydroxamide (13j)

To a solution of compound 12j (125 mg, 0.281 mmol) in 1,4-dioxane (2 mL)were added hydroxylamine hydrochloride (194 mg, 2.80 mmol) and a freshlyprepared solution of sodium methoxide in methanol (96 mg, 4.20 mmol ofsodium dissolved in 1 mL of methanol) under a N₂ atmosphere. Thereaction mixture was stirred at room temperature for 2 h. The reactionmixture was acidified to pH˜6 with 1M HCl and the formed precipitateswere filtered off. The filtrate was diluted with ethyl acetate (5 mL)and water (2 mL) and the organic layer was separated. The aqueous layerwas washed with ethyl acetate (5 mL) and the combined organic layerswere dried on sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by preparative HPLC to give 13j (9mg, yield 7.2%). HPLC: 97.51% Rt=14.61 min).

¹H NMR (CD₃OD, 200 MHz) δ: 7.91 (1H, s), 7.76-7.41 (9H, m), 3.69 (4H,m), 3.21 (4H, m).

MS (m/z): 445 (M+1).

Preparation of2-[4-(5-dimethylamino-naphthalene-1-sulfonyl)-piperazin-1-yl]-thiazole-5-carboxlicacid methyl ester (12k)

To a solution of compound II (200 mg, 0.886 mmol) in dichloromethane(7.5 mL) were added 5-dimethylamino-naphthalene-1-sulfonyl chloride (356mg, 1.320 mmol) and triethylamine (220 mg, 2.169 mmol) under N₂atmosphere. The reaction mixture was stirred at room temperature for 4h. Water (10 mL) followed by dichloromethane (10 mL) were added to thereaction mixture and the organic layer was separated, dried on sodiumsulphate, filtered and concentrated under reduced pressure. The residuewas purified by column chromatography using silica gel to give thecompound 12k as a solid (233 mg, 57.50%). HPLC: 99.04% (Rt=12.33 min).

¹H NMR (CDCl₃, 200 MHz) 5; 8.59 (1H, d, J=8.4 Hz), 8.37 (1H, d, J=8.4Hz), 8.21 (1H, d, J=7.4 Hz), 7.80 (1H, s), 7.55 (2H, m), 7.19 (1H, d,J=7.4 Hz), 3.80 (3H, s), 3.62 (4H, t, J=5.6 Hz), 3.32 (4H, t, J=5.6 Hz),2.88 (6H, s).

MS (m/z): 460 (M+1).

Preparation of2-[4-(5-dimethylamino-naphthalene-1-sulfonyl)-piperazin-1-yl]-thiazole-5-carboxylicacid hydroxyamide (13k)

To a solution of compound (12k) (125 mg, 0.270 mmol) in 1,4-dioxane (2mL) were added hydroxylamine hydrochloride (187 mg, 2.70 mmol) and afreshly prepared solution of sodium methoxide in methanol (92 mg, 4.00mmol of sodium dissolved in 1 mL of methanol) under a N₂ atmosphere. Thereaction mixture was stirred at room temperature for 2 h (progress ofthe reaction was monitored by TLC analysis). The reaction mixture wasacidified to pH 6 with 1M HCl and the formed precipitates were filteredoff. The filtrate was diluted with ethyl acetate (5 mid) and water (2mL) and the organic layer was separated. The aqueous layer was washedwith ethyl acetate (5 mL) and the combined organic layers were dried onsodium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by preparative HPLC to give 13k (10 mg, yield8.0%). HPLC: 90.69% (Rt=12.77 min).

¹H NMR (CD₃OD, 200 MHz) δ: 8.12 (2H, m), 8.33 (1H, m), 7.86-7.59 (4H,m), 3.62 (4H, m), 3.36 (4H, m), 3.16 (6H, s).

Example 15

Preparation of2-[4-(4-fluoro-benzene-sulfonyl)-piperazin-1-yl]-thiazole-5-carboxylicacid methyl ester (12m)

To a solution of compound II (200 mg, 0.886 mmol) in dichloromethane(7.5 mL) were added 4-fluorobenzene-sulfonyl chloride (256 mg, 1.320mmol) and triethylamine (220 mg, 2.169 mmol) under a N₂ atmosphere. Thereaction mixture was stirred at room temperature for 4 h. Water (10 mL)followed by dichloromethane (10 mL) were added to the reaction mixtureand the organic layer was separated, dried on sodium sulfate, filteredand concentrated under reduced pressure. The residue was purified bycolumn chromatography using silica gel to give the compound 12m as asolid (300 mg, 88.4%). HPLC: 86.16% (Rt=7.72 min).

¹H NMR (CDCl₃, 200 MHz) δ: 7.82 (IS Hs), 7.78-7.75 (2H, m), 7.23 (211,d, J=8.8 Hz), 3.81 (3H, s), 3.69 (4H, t, J=4.8 Hz), 3.14 (4H, t, JA 4.8Hz).

MS (m/z): 385(M+1), 101.

Preparation of2-[4-(4-fluoro-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylicacid hydroxyamide (13m)

To a solution of compound (12m) (125 mg, 0.320 mmol) in 1,4-dioxane (2mL) were added hydroxylamine hydrochloride (225 mg, 3.20 mmol) and afreshly prepared solution of sodium methoxide in methanol (110 mg, 4.80mmol of sodium dissolved in 1 mL of methanol) under a N₂ atmosphere. Thereaction mixture was stirred at room temperature for 2 h (progress ofthe reaction was monitored by TLC analysis). The reaction mixture wasacidified to pH˜6 with 1M HCl and the formed precipitates were filteredoff. The filtrate was diluted with ethylacetate (5 mL) and water (2 mL)and the organic layer was separated. The aqueous layer was washed withethylacetate (5 mL) and the combined organic layers were dried on sodiumsulphate, filtered and concentrated under reduced pressure. The residuewas purified by preparative HPLC to give 13m.

HPLC: (Rt=3.89 min).

Example 16

Preparation of 2-(4-methyl-piperazin-1-yl)-thiazole-5-carboxylic acidmethyl ester (15a)

To a solution of methyl 2-bromothiazole-5-carboxylate 1 (222 mg, 1.00mmol) in acetonitrile (20 mL) were added N-methyl piperazine 14a (120mg, 1.20 mmol) and potassium carbonate (152 mg, 1.10 mmol) under a N₂atmosphere. The reaction mixture was heated to reflux at 80° C. for 10h. The reaction mixture was filtered through Celite and the filtrate wasconcentrated under reduced pressure. The residue was purified by columnchromatography using silica gel to give the compound 16a (188 mg,78.1%).

¹H NMR (CD₃OD, 200 MHz) δ: 7.93 (1H, s), 3.83 (3H, s), 3.67 (4H, m),2.75 (4H, t, J=5.0 Hz), 2.49 (3H, s).

MS (m/z): 242 (M+1).

Preparation of 2-(4-methyl-piperazin-1-yl)-thiazole-5-carboxylic acidhydroxyamide (16a)

To a solution of compound 15a (125 mg, 0.518 mmol) in 1,4-dioxane (2 mL)were added hydroxylamine hydrochloride (360 mg, 5.18 mmol) and a freshlyprepared solution of sodium methoxide in methanol (178 mg, 7.72 mmol ofsodium dissolved in 1.5 mL of methanol) under a N₂ atmosphere. Thereaction mixture was stirred at room temperature for 2 h. The reactionmixture was acidified to pH 6 with 1M HCl and the formed precipitateswere filtered off. The filtrate was diluted with ethyl acetate (5 mL)and water (2 mL) and the organic layer was separated. The aqueous layerwas washed with ethyl acetate (5 mL) and the combined organic layerswere dried on sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by preparative HPLC to give 16a.

HPLC: (Rt=10.74 min).

Example 17

Preparation of 2-(4-Benzyl-piperazin-1-yl)-thiazole-5-carboxylic acidmethyl ester

To a solution of methyl 2-bromothiazole-5-carboxylate 1 (222 mg, 1.00mmol) in acetonitrile (20 mL) were added N-benzyl piperazine 14b (211mg, 1.20 mmol) and potassium carbonate (152 mg, 1.10 mmol) under a N₂atmosphere. The reaction mixture was heated to reflux at 80° C. for 10h. The reaction mixture was filtered through Celite and the filtrate wasconcentrated under reduced pressure. The residue was purified by columnchromatography using silica gel to give the compound 15b (229 mg,72.7%).

¹H NMR (CD₃OD, 200 MHz) δ: 7.87 (1H, s), 7.40 (5H, m), 3.84 (3H, s),3.61 (6H, m), 2.60 (4H, t, J=5.0 Hz).

MS (m/z): 318 (M+1).

Preparation of 2-(4-Benzyl-piperazin-1-yl)-thiazole-5-carboxylic acidhydroxyamide (16b-hydroxamate)

To a solution of compound 15b (125 mg, 0.394 mmol) in 1,4-dioxane (2 mL)were added hydroxylamine hydrochloride (273 mg, 3.94 mmol) and a freshlyprepared solution of sodium methoxide in methanol (136 mg, 5.911 mmol ofsodium dissolved in 1.5 mL of methanol) under N₂ atmosphere. Thereaction mixture was stirred at room temperature for 2 h. The reactionmixture was acidified to pH 6 with 1M HCl and the formed precipitateswere filtered off. The filtrate was diluted with ethyl acetate (5 mL)and water (2 mL) and the organic layer was separated. The aqueous layerwas washed with ethyl acetate (5 mL) and the combined organic layerswere dried on sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by preparative HPLC to give 16b.

HPLC: (Rt=4.45 min).

Example 18

Preparation of2-[4-(2-hydroxyethyl)-piperazin-1-yl]-thiazole-5-carboxylic acid methylester (15c)

To a solution of methyl 2-bromothiazole-5-carboxylate 1 (222 mg, 1.00mmol) in acetonitrile (20 mL) were added N-(2-hydroxyethyl)piperazine14c (156 mg, 1.20 mmol) and potassium carbonate (152 mg, 1.10 mmol)under a N₂ atmosphere. The reaction mixture was heated to reflux at 80°C. for 10 h. The reaction mixture was filtered through Celite and thefiltrate was concentrated under reduced pressure. The residue waspurified by column chromatography using silica gel to give the compound15c (185 mg, 68.2%).

¹H NMR (CD₃OD, 200 MHz) δ: 7.81 (1H, s), 3.79 (3H, s), 3.70 (2H, t,J=5.4 Hz), 3.63 (4H, t, J=5.6 Hz), 2.70 (6H, m).

MS (m/z): 272 (M+1).

Preparation of2-(4-(2-hydroxyethyl)-piperazin-1-yl)-thiazole-5-carboxylic acidhydroxyamide (16c)

To a solution of compound 15c (125 mg, 0.461 mmol) in 1,4-dioxane (2 mL)were added hydroxylamine hydrochloride (320 mg, 4.61 mmol) and a freshlyprepared solution of sodium methoxide in methanol (159 mg, 6.91 mmol ofsodium dissolved in 1.5 mL of methanol) under a N₂ atmosphere. Thereaction mixture was stirred at room temperature for 2 h. The reactionmixture was acidified to pH˜6 with 1M HCl and the formed precipitateswere filtered off. The filtrate was diluted with ethyl acetate (5 mL)and water (2 mL) and the organic layer was separated. The aqueous layerwas washed with ethyl acetate (5 mL) and the combined organic layerswere dried on sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by preparative HPLC to give 16c.

HPLC: (Rt=2.97 min).

Example 19

Preparation of 2-[4-(2-aminoethyl)-piperazin-1-yl]-thiazole-5-carboxlicacid methyl ester (15d)

To a solution of methyl 2-bromothiazole-5-carboxylate 1 (222 mg, 1.00mmol) in acetonitrile (20 mL) were added N-(2-amino ethyl)piperazine 14d(155 mg, 1.20 mmol) and potassium carbonate (152 mg, 1.10 mmol) under aN₂ atmosphere. The reaction mixture was heated to reflux at 80° C. for10 h. The reaction mixture was filtered through Celite and the filtratewas concentrated under reduced pressure. The residue was purified bycolumn chromatography using silica gel to give the compound 15d (176 mg,65.2%).

¹H NMR (CD₃OD, 200 MHz) δ: 7.82 (1H, s), 7.23 (5H, m), 3.81 (3H, s),3.60 (4H, t, J=5.0 Hz), 2.90-2.63 (8H, m).

Preparation of 2-(4-(2-aminoethyl)-piperazin-1-yl)-thiazole-5-carboxylicacid hydroxyamide (16d)

To a solution of compound 15d (125 mg, 0.462 mmol) in 1,4-dioxane (2 mL)were added hydroxylamine hydrochloride (321 mg, 4.62 mmol) and a freshlyprepared solution of sodium methoxide in methanol (159 mg, 6.91 mmol ofsodium dissolved in 1.5 mL of methanol) under a N₂ atmosphere. Thereaction mixture was stirred at room temperature for 2h. The reactionmixture was acidified to pH˜6 with 1M HCl and the formed precipitateswere filtered off. The filtrate was diluted with ethylacetate (5 mL) andwater (2 mL) and the organic layer was separated. The aqueous layer waswashed with ethylacetate (5 mL) and the combined organic layers weredried on sodium sulphate, filtered and concentrated under reducedpressure. The residue was purified by preparative HPLC to give 16d.

HPLC: (Rt=293 min).

Example 20

Preparation of 2-[4-phenylethyl-piperazin-1-yl]-thiazole-5-carboxylicacid methyl ester (15e)

To a solution of methyl 2-bromothiazole-5-carboxylate 1 (222 mg, 1.00mmol) in acetonitrile (20 mL) were added N-phenyl ethyl piperazine 14e(228 mg, 1.20 mmol) and potassium carbonate (152 mg, 1.10 mmol) under aN₂ atmosphere. The reaction mixture was heated to reflux at 80° C. for10 h. The reaction mixture was filtered through Celite and the filtratewas concentrated under reduced pressure. The residue was purified bycolumn chromatography using silica gel to give the compound 15c (245 mg,66.4%).

¹HNMR (CD₃OD, 200 MHz); 67.78 (i, Hs), 3.81 (3H, s), 3.62 (4H, m),2.77-2.31 (8H, m).

Preparation of 2-(4-phenylethyl-piperazin-1-yl)-thiazole-5-carboxylicacid hydroxyamide (16e)

To a solution of compound 15e (125 mg, 0.377 mmol) in 1,4-dioxane (2 mL)were added hydroxylamine hydrochloride (262 mg, 3.77 mmol) and a freshlyprepared solution of sodium methoxide in methanol (130 mg, 5.655 mmol ofsodium dissolved in 1.5 mL of methanol) under a N₂ atmosphere. Thereaction mixture was stirred at room temperature for 2 h. The reactionmixture was acidified to pH˜6 with 1 M HCl and the formed precipitateswere filtered off. The filtrate was diluted with ethyl acetate (5 mL)and water (2 mL) and the organic layer was separated. The aqueous layerwas washed with ethyl acetate (5 mL) and the combined organic layerswere dried on sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by preparative HPLC to give 16e.

HPLC: (Rt=13.41 min).

Example 20B

2-(4-(2-oxo-2-phenylethyl #piperazin-1-yl)-1,3-thiazole-5-carboxylicacid hydroxyamide

A mixture of intermediate ester 11 (Scheme 8) (115 mg, 0.504 mmol),α-bromoacetophenone (128 mg, 0.604 mmol), cesium carbonate (326 mg, 1.0mmol) and DCM was stirred at room temperature for 12 hours. The reactionwas poured into water and extracted with DCM (20 mL). The solvent wasdried, the solvent evaporated, and the residue chromatographed using 50%ethyl acetate in hexanes to give the intermediate alkylated ester (120mg, 67%); MS 360 (M+H⁺).

The alkylated ester (100 mg, 0.278 mmol) in methanol (5 mL) at 0° C. wastreated with 50% aqueous hydroxylamine (1 mL) and aqueous sodiumhydroxide (80 mg in 0.5 mL of water) and stirred for 4 hours. Thereaction was acidified with hydrochloric acid (6N) and the solvent wasremoved to obtain a solid that was purified by preparative HPLC to giveExample 20B. ¹H NMR (CDCl₃, 300 MHz) δ: 7.69 (d, J=8.1 Hz, 2H), 7.28 (d,J=8.1 Hz, 2H), 4.57 (s, 2H), 3.74 (m, 4H), 3.37 (m, 4H), 2.27 (s, 3H).

Example 21

Preparation of 2-(4-acetyl-piperazin-1-yl)-thiazole-5-carboxylic acidmethyl ester (22a)

1 NMR (CDCl₃, 200 MHz) δ: 7.82 (1H, s), 3.84 (3H, s), 3.77 (4H, t, J=5.4Hz), 3.54 (4H, t, J=5.4 Hz), 2.15 (3H, s).

Preparation of 2-(4-acetyl-piperazin-1-yl)-thiazole-5-carboxylic acidhydroxamide

To a solution of compound 22a (100 mg, 0.300 mmol) in 1,4-dioxane (2 mL)were added hydroxylamine hydrochloride (208 mg, 2.991 mmol) and afreshly prepared solution of sodium methoxide in methanol (103 mg, 4.511mmol of sodium dissolved in 1.5 mL of methanol) under a N₂ atmosphere.The reaction mixture was stirred at room temperature for 2 h. Thereaction mixture was acidified to pH˜6 with 1M HCl and the formedprecipitates were filtered off. The filtrate was diluted with ethylacetate (5 mL) and water (2 mL) and the organic layer was separated. Theaqueous layer was washed with ethyl acetate (5 ml) and the combinedorganic layers were dried on sodium sulfate, filtered and concentratedunder reduced pressure. The residue was purified by preparative HPLC togive 23a. HPLC: Rt=4.42 min.

Example 22

Preparation of 2-(4-benzoyl-piperazin-1-yl)-thiazole-5-carboxylic acidmethyl ester (22b)

To a solution of compound 21 (200 mg, 0.886 mmol) in dichloromethane(7.5 mL) were added benzoyl chloride (148 mg, 1.056 mmol) andtriethylamine (106 mg, 1.047 mmol) under a N₂ atmosphere. The reactionmixture was stirred at room temperature for 4 h (progress of thereaction was monitored by TLC analysis). Water (10 mL) followed bydichloromethane (10 mL) were added to the reaction mixture and theorganic layer was separated, dried on sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by columnchromatography using silica gel to give the compound 22b (180 mg, yield61.8%).

Preparation of 2-(4-benzoyl-piperazin-1-yl)-thiazole-5-carboxylic acidhydroxamide (23b)

To a solution of compound 22b (100 mg, 0.321 mmol) in 1,4-dioxane (2 mL)were added hydroxylamine hydrochloride (222 mg, 3.191 mmol) and afreshly prepared solution of sodium methoxide in methanol (110 mg, 4.712mmol of sodium dissolved in 1.5 mL of methanol) under a N2 atmosphere.The reaction mixture was stirred at room temperature for 2 h. Thereaction mixture was acidified to pH˜6 with 1M HCl and the formedprecipitates were filtered off. The filtrate was diluted with ethylacetate (5 mL) and water (2 mL) and the organic layer was separated. Theaqueous layer was washed with ethyl acetate (5 mL) and the combinedorganic layers were dried on sodium sulfate, filtered and concentratedunder reduced pressure. The residue was purified by preparative HPLC togive 23b. HPLC: Rt=3.69 nm in.

Example 23

Preparation of 2-(4-phenylacetyl-piperazin-1-yl)-thiazole-5-carboxylicacid methyl ester (22c)

To a solution of compound 21 (200 mg, 0.886 mmol) in dichloromethane(7.5 mL) were added phenyl acetyl chloride (162 mg, 1.056 mmol) andtriethylamine (106 mg, 1.047 mmol) under a N₂ atmosphere. The reactionmixture was stirred at room temperature for 4 h (progress of thereaction was monitored by TLC analysis). Water (10 mL) followed bydichloromethane (10 mL) were added to the reaction mixture and theorganic layer was separated, dried on sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by columnchromatography using silica gel to give the compound 22c (130 mg, yield42.9%). HPLC: 99.40 0% (Rt=11.93 min).

¹H NMR (CDCl₃, 200 MHz) δ: 7.85 (1H, s), 7.27 (5H, m), 3.82 (3H, s),3.73 (4H, m), 3.51 (4H, m), 3.34 (2H, m).

Preparation of 2-(4-phenylacetyl-piperazin-1-yl)-thiazole-5-carboxylicacid hydroxamide (23c)

To a solution of compound 22c (100 mg, 0.377 mmol) in 1,4-dioxane (2 mL)were added hydroxylamine hydrochloride (208 mg, 3.771 mmol) and afreshly prepared solution of sodium methoxide in methanol (103 mg, 4.471mmol of sodium dissolved in 1.5 mL of methanol) under a N₂ atmosphere.The reaction mixture was stirred at room temperature for 2 h, Thereaction mixture was acidified to pH˜6 with 1M HCl and the formedprecipitates were filtered off. The filtrate was diluted with ethylacetate (5 mL) and water (2 mL) and the organic layer was separated. Theaqueous layer was washed with ethyl acetate (5 mL) and the combinedorganic layers were dried on sodium sulfate, filtered and concentratedunder reduced pressure. The residue was purified by preparative HPLC togive 23c. HPLC: Rt=5.62 min.

Example 23b

2-[4-(3-{1H-indol-3-yl}propanoyl)-piperazin-1-yl]-1,3-thiazole-5-carboxylicacid hydroxyamide

To a solution of 21 (100 mg, 0.440 mmol) in tetrahydrofuran (10 mL) wasadded EDCI (92 mg, 0.480 mmol), 1-hydroxy-7-azabenzotriazole (HOAT) (65mg, 0.478 mmol), DIEA (75 mg, 0.564 mm) and indole-3-propionic acid (83mg, 0.440 mmol) under N₂ atmosphere. The reaction mixture was stirred atroom temperature for 12 h. Water (10 nm) followed by dichloromethane (10mL) were added to the reaction mixture and the organic layer wasseparated, dried over sodium sulfate, filtered and concentrated underreduced pressure. The residue obtained was purified by columnchromatography using silica gel to obtain compound amide 22 (120 mg). ¹HNMR (CDCl₃, 200 MHz) 6; 7.99 (1H, s), 7.85 (1H, s), 7.63-7.05 (5H, m),3.83 (3H, s), 3.74 (4H, t, J=5.2 Hz), 3.42 (4H, t, JA 5.2 Hz), 3.18 (2H,t, J=7.2 Hz), 2.75 (2H, t, J=7.2 Hz).

To a solution of the amide 22 (100 mg, 0.25 mmol) in 1,4-dioxane (2 mL)were added hydroxylamine hydrochloride (174 mg, 2.51 mmol) and a freshlyprepared solution sodium methoxide in methanol (86 mg, 3.73 mmol ofsodium dissolved in 1.5 mL of methanol) under N₂ atmosphere. Thereaction mixture was stirred at room temperature for 2 h. The reactionmixture was acidified to pH˜6 with 1M HCl and the precipitates werefiltered off. The filtrate was diluted with ethylacetate (5 mL) andwater (2 mL) and the organic layer was separated. The aqueous layer waswashed with ethylacetate (5 mL) and the combined organic layers weredried on sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by preparative HPLC to give Example23b; m/c=400 (M+H⁺).

Example 24

Preparation of N-(2-napthylsulfonyl)piperazine (25)

A solution of N-tert-butyoxycarbonylpiperazine (2a) (1.86 g) in DCM(1001 mL) and N,N-di-2-propyl-ethylamine (2 mL) was cooled in ice-wateras a solution of 2-naphthalenesulfonylchloride (2.27 g) in DCM (50 mL)was added drop-wise. After addition, the cooling was removed and thereaction stirred overnight. The solvent was evaporated and the residuepartitioned between water and ethyl acetate. The organic phase wassequentially washed with 0.5 N hydrochloric acid, water, saturatedaqueous sodium bicarbonate and brine. After drying, the solvent wasevaporated to provide a white solid. The white solid was dissolved inDCM (35 mL) and treated with trifluoroacetic acid (15 mL). After onehour, the solvent was evaporated, the residue suspended in water and thesolution made basic with 1 N sodium hydroxide. The mixture was extractedwith ethyl acetate. The extracts were washed with water, dried, and thesolvent evaporated to give a white solid (2.7 g).

¹HNMR (CD₃OD, 300 MHz) δ: 8.41 (s, 1H), 8-8.13 (3H, m), 7.6-7.8 (3H, m),3.17-3.21 (4H, m), 3.09-3.13 (4H, m).

Preparation of N-(2-naphthylsulfonyl)-N-(2-acetamido)piperazine (26)

A mixture of 25 (2.2 g), 2-bromoacetamide (1.15 g) potassium carbonate(1.16 g) and ethanol (40 mL) was heated to reflux overnight. The solventwas evaporated and the residue suspended in water and stirred for 30minutes. The solid was collected by filtration and thoroughly dried togive a white solid (2.8 g).

hu 1H NMR (CD₃OD, 300 MHz) δ: 8.39 (s, 1M, 7.99-8.11 (m, 3H), 7.63-7.79(m, 3H), 3.14 (m, 4H), 2.98 (s, 2H), 2.60 (t, 4H).

Preparation of N-(2-naphthylsulfonyl)-N′-(2-thioacetamido)piperazine(27)

A suspension of 26 (0.94 g) in tetrahydrofuran (10 mL) was stirred asphosphorus pentasulfide (1.89 g) was added in portions. The reaction wasthen heated to reflux for one hour. The solvent was decanted and thesolid residue triturated with tetrahydrofuran. The solvent wasevaporated from the extracts and the residue purified by flashchromatography on 30 g of silica gel eluting with 1:1 ethylacetate:hexane. The desired component was finally eluted with 60% ethylacetate-hexane. Evaporation of the pure fractions gave a white solid(0.23 g).

¹H NMR(CD₃OD, 300 MHz) δ: 8.27 (s, 1H), 7.88-8.0 (m, 3H), 7.52-7.68 (m,3H), 3.23 (s, 2H), 3.03 (m, 4H), 2.46 (t, 4H).

MS (EI+): 350 (m+1).

Preparation of Methyl Chloro(Formyl)Acetate

Methyl chloroacetate (3.2 g) and methyl formate (1.8 g) were dissolvedin toluene (5 mL) and the mixture was cooled in ice-water. Sodiummethoxide (2 g) was added in portions and the reaction stirred for fivehours. The reaction was quenched with water (100 mL) and the mixture wasextracted with toluene (100 mL) and ether (100 mL). The aqueous layerwas separated, cooled in ice-water, and the pH of the solution adjustedto 4 using 6 N hydrochloric acid. The aqueous layer was then extractedwith ethyl acetate. The organic extracts were dried and the solventthoroughly evaporated to give a tacky solid (2 g) that was used withoutfurther purification. TLC on silica gel eluting with 1:1 ethylacetate:hexane shows two spots R_(f)=0.36 and 0.38.

Preparation of N-(2-naphthylsulfonyl)-N′-[2-(5-carbomethoxy)thiazolyl]piperazine (28)

A mixture of 27 (84 mg) and methyl chloro(formyl)acetate (180 mg) intoluene (3 mL) was heated to reflux for three hours. The reaction wasdiluted with ethyl acetate and washed sequentially with aqueous,saturated sodium bicarbonate, 10% aqueous potassium carbonate and water.The organic layer was dried and the solvent evaporated to give a brown,oily residue. The residue was purified by flash chromatography on silicagel (15 g) eluting with 1:1 ethyl acetate:hexane. The desired fractionswere eluted with 60% ethyl acetate-hexane. Evaporation of the purestfraction gave a brown glass (40 mg).

¹H NMR (CDCl₃, 300 MHz) δ: 8.33 (s, 1H), 8.23 (s, 1H), 7.92-8.0 (m, 3H),7.6-7.76 (m, 3H), 3.836 (s, 3H), 3.828 (s, 2H), 3.15 (m, 4H), 2.71 (m,4H).

MS (EI+): 432 (m+1).

Preparation ofN-(2-naphthylsulfonyl)-N′-{2-[5-(N-hydroxycarboxamido)]thiazolyl}-piperazine(29)

A solution of 28 (32 mg) in ethanol (1.5 mL) was cooled in ice-water. Asolution of 50% aqueous hydroxylamine (50 μL) was added followed by 1 Nsodium hydroxide (53 μL). After four hours, the cooling was stopped andthe reaction stirred overnight. Additional 50% hydroxylamine (25 μL) and1 N sodium hydroxide (20 μL) were added and stirring continued for eighthours. The reaction was neutralized with 1 N hydrochloric acid (70 μL)and the solvent was evaporated to give a yellowish solid. This productwas purified by HPLC using a 19×50 mm C-18 column eluting with a tenminute linear gradient that started with 100% water-0.1% trifluoroaceticacid and ended with 30% water-0.1% trifluoroacetic acid/70%acetonitrile-0.1% trifluoroacetic acid. The pure fractions of thecomponent eluting at 4.8 minutes were freeze dried to give a white solid(0.1 mg).

MS (EI+): 433 (m+1).

Example 25

2-[1-(1,1′-biphenyl-4-ylsulfonyl)piperidin-4-yl]-1,3-thiazole-5-carboxylicacid hydroxyamide

A mixture of tertiary butyl4(aminocarbothioyl)tetrahydropyridine-1(2H)carboxylate 25.1 (1 g) andmethyl chloro(formyl)acetate (1.3 g) in toluene (20 mL) was heated in an80°-90° C. oil bath for 1.75 hours. Another spatula full of thechloro(formyl)acetate was added and the heating continued another hour.The reaction was cooled and partitioned between saturated aqueous sodiumbicarbonate and ethyl acetate. The organics were washed with water andbrine. Drying and evaporation of the solvent gave an oily residue thatwas purified by flash chromatography eluting with 30% ethyl acetatehexane to give the thiazole 25.2 as a yellow oil (0.6 g).

A solution of 25.2 (0.55 g) in methylene chloride (3 mL) was treatedwith trifluoroacetic acid (1 mL). After three hours, another portion oftrifluoroacetic acid (1 mL) was added and stirring continued for threehours. The solvent was evaporated and the residue partitioned betweenwater and ether. The aqueous phase was made basic with 1 N sodiumhydroxide and extracted with chloroform. The chloroform solution wasdried and the solvent evaporated to give 25.3 as a dark gum (0.187 g). Asolution of the gum in methylene chloride (5 mL) anddiisopropylethylamine (0.3 mL) was cooled in ice-water and treated with4-biphenylsulphonyl chloride (0.21 g) in methylene chloride (2 mL). Thecooling was removed and the reaction stirred one hour. A crystal of4-dimethylaminopyridine was added and stirring was continued overnight.The solvent was evaporated and the residue partitioned between water andethyl acetate. The organics were washed with 1 N hydrochloric acid,aqueous saturated sodium bicarbonate, and brine. The solvent was driedand evaporated to give a tan solid. The solid was purified by flashchromatography eluting with 60-80% ethyl acetate-hexane to give 25.3 asa tan powder (91 mg) with the expected m/e of 443 (M+H⁺).

A mixture of methyl2-[1-(1,1′-biphenyl-4-ylsulfonyl)piperidin-4-yl]-1,3-thiazole-5-carboxylate25.3 (9 mg), 50% hydroxylamine in water (0.05 mL), and dioxane (1 mL)were cooled in ice-water. To the reaction was added 1N sodium hydroxide(0.053 mL) followed by removal of the cooling bath. After stirringovernight, the reaction was neutralized with 1 N hydrochloric acid(0.053 mL) and the solvent evaporated. The residue was purified bypreparative hplc to give Example 25 as a floculant white solid (3.5 mg).¹H NMR (DMSO) δ: 2.75 (m, 2H), 2.15 (m, 2H), 2.5 (m, 2H), 3.1 (m, 1H),3.75 (m, 2H), 7.45-7.55 (m, 3H), 7.72-7.96 (m, 6H), 8.08 (s, 1H), 11.3(s, 1H); m/e=444 (M+H⁺).

BIOLOGICAL EXAMPLES Example A In vitro fluorescent histone deacetylaseassay

Histone deacetylase (HDAC) activity assays were performed using the HDACfluorescent activity assay/drug discovery kit (Biomol ResearchLaboratories, Plymouth Meeting, Pa.) essentially according to themanufacturer's instructions. The included HeLa cell nuclear extract,which contains a mosaic of HDAC enzymes and other nuclear factors, wasused as the source of HDAC activity. The final substrate concentrationin the assay mixture was 50 μM. The reaction was allowed to proceed for10 min at room temperature before stopping the reaction. Test compoundswere prepared as 20 mM stock solutions in DMSO (Molecular Biology grade,Sigma-Aldrich Co., St. Louis, Mo.) and stored at −70° C. Serialdilutions of test compounds were prepared in assay buffer immediatelyprior to testing. DMSO was determined in a separate trial to have nosignificant effect on the activity of this assay at concentrations up to5%; the final DMSO concentration in the wells was no more than 2% andtherefore DMSO effects were safely neglected. Assays were performed inwhite polystyrene 96-well half-area assay plates (Corning, Corning,N.Y.) and measured on a Wallace 1420 fluorescent plate reader (WallacOy, Turku, Finland) with an excitation wavelength of 355 nm, an emissionwavelength of 460 nm, and a 1 sec signal averaging time.

In some assays recombinant HDAC8 (Biomol) was used as the source of theenzyme activity; here the final substrate concentration was 250 μM, thefinal concentration of HDAC8 was 0.02 u/μL and the reaction was allowedto proceed at 37° C. for 1 h before stopping. For all curves, IC₅₀values were calculated with the GraFit curve-fitting program (Erithacus,Horley, Surrey, UK).

The HDAC inhibition data for representative examples of this inventionis presented in Table 1.

TABLE 1 HDAC inhibition potencies for selected examples of the presentinvention Example No. IC₅₀ HDAC Inhibition (μM)  2 5.9  4 0.045  4b 0.44 4c 0.16  4d 0.4  4e 3.24  4f 0.55  4g 14.5  4h 1.63  4i 0.65  4j 11.4 4k 318  4m 4.7  5 0.05  5b 4.7  5c 12.6  5d 8.4  5e 2.15  5f 18.8  5g0.6  5h 0.67 16 671 17 755 18 7.7 20 118 20B 0.33 21 2.75 22 3.5 23 31.623b 0.87 24 6.9 25 13.1

Example B Whole Cell Cytotoxicity Assay:Sulforhodamine B

The following procedure can be found on the Developmental TherapeuticsProgram NCI/NIH web site athttp:dtp.nci.nih.gov/brancehes/btb/ivclsp.html.

1. Human tumor cell lines of HT29, A549 and MCF7 are grown in DNEMcontaining 10% fetal bovine serum and 2 mM L-glutamine. Cells are platedin a 96 well plate at a density of 5000 cells per well in 100 μL ofgrowth medium and incubated at 37° C., 5% CO₂, for 24 hours prior to theaddition of experimental compounds

2. Experimental drugs are solubilized in DMSO for a final concentrationof 20 mM immediately prior to use. Drugs are farther diluted in growthmedia for a total of nine drug concentrations and a growth control. Atthe 24-hour time point, one plate of cells is fixed in situ with TCA asa measurement of the cell population at time zero, or the time of drugaddition.

3. The plates are further incubated with drug for an additional 48hours.

4. The cells are fixed in situ by gently aspirating off the culturemedia and then adding 50 μL of ice cold 10% TCA per well and incubatedat 4° C. for 60 minutes. The plates are washed with tap water five timesand allowed to air dry for 5 minute.

5. 50 μl of a 0.4% (w/v) Sulforhodamine B solution in 1% (v/v) aceticacid is added per well and incubated for 30 minutes at room temperature.

6. Following staining, plates are washed five times with 1% acetic acidto remove any unbound dye and then allowed to air dry for 5 minutes.

7. Stain is solubilized with 100 μL of 10 mM Tris pH 10.5 per well andplaced on an orbital rotator for 5 minutes.

8. Absorbance is read at 570 nm. Representative GI₅₀'s against MCF7cells for selected examples of this invention are shown in Table 2.

TABLE 2 Activity of selected examples of this invention against MCF7cells Example No. GI₅₀ in MCF7 cells (μM)  2 10  4 0.7  4b 3  4c 4  4d 1 4e 6  4f 2  4g 3  4h 5  4i 18  4j 1.5  4k 4  4m 2.5  5 6  5b 10  5c  5d15  5e 2  5f 20  5g 8  5h 3.5 16 17 4 18 20 20B 4 21 22 40 23 20 23b 3024 10 25 100

1. A compound of formula I:

wherein: R is selected from the group consisting of hydrogen, aryl,substituted aryl, heteroaryl substituted heteroaryl, alkyl andsubstituted alkyl; R¹² is selected from the group consisting of —NR¹⁴OH,—OH, —NR¹⁴R¹⁵, —OR¹⁴, —(C₁-C₆)alkylene-SR⁴, —(C₁-C₆)alkylene-OR¹⁴,—(C₁-C₆)alkylene-NR¹⁴R¹⁵, —CF₃; where R¹⁴ and R¹⁵ are independentlyselected from the group consisting of hydrogen, (C₁-C₆)alkyl,(C₁-C₆)substituted alkyl, aryl, substituted aryl and where R¹⁴ and R¹⁵together with the nitrogen atom bound thereto form a heterocyclic orsubstituted heterocyclic ring; V, W, X, Y, and Z form a 5-memberedheteroaryl where W, X, and Y are independently selected from ═C(R¹¹)—,—N═, —N(R¹⁴)—, —O—, —S—, —S(O)—, and/or —S(O)₂—, and V and Zindependently form ═C(R¹⁴)— and/or >N— where R¹⁴ is as defined above,provided that at least one of V, W, X, Y and Z is ═C(R¹⁴)—, and furtherprovided that the ring formed by V, W, X, Y, and Z is not a thiophene;R¹¹ is hydrogen or alkyl; the ring defined by A above is selected fromthe group consisting of cycloakylene, substituted cycloalkylene,hetrocyclene, substituted heterocyclene, arylene, heteroarylene,-het-(L²)_(b)-het-, -het-(L²)_(b)-cyclo-, -cyclo-(L²)_(b)-het-, and-cyclo-(L²)_(b)-cyclo-; where each b is independently 0 or 1; L² isselected from the group consisting of a covalent bond, (C₁-C₄)alkylene,substituted (C₁-C₄)alkylene, —NH(C₁-C₄)alkylene, (C₁-C₄)alkyleneNH—,provided that the nitrogen atom of the —NH(C₁-C₄)alkylene and(C₁-C₄)alkyleneNH— group are not attached to a nitrogen atom in the hetor in cyclo groups; T is selected from the group consisting of—SO₂—[(C₁-C₃)alkylene]_(p)-, —[(C₁-C₃)alkylene]_(p)-SO₂—,—NR¹⁶SO₂—[(C₁-C₃)alkylene]_(p)—, —SO₂NR¹⁶—[(C₁-C₃)alkylene]_(p)-,—C(O)—[(C₁-C₃)alkylene]_(p)-, —[(C₁-C₃)alkylene]_(p)-C(O)—,—NR⁶C(O)—[(C₁-C₃)alkylene]_(p)-, —C(O)NR¹⁶—[(C₁-C₃)alkylene]_(p)-,—N(R¹⁶)—[(C₁-C₃)alkylene]_(p) and (C₁-C₃)alkylene where p is zero or oneand R¹⁶ is hydrogen, alkyl, aryl, or heteroaryl, provided that when T isconnected to A at a nitrogen atom and T is—SO₂NR¹⁶—[(C₁-C₃)alkylene]_(p)—, —C(O)NR¹⁶—[(C₁-C₃)alkylene]_(p)—, or—N(R¹⁶)—[(C₁-C₃)alkylene]_(p) then p is not zero; Q is selected from thegroup consisting of a covalent bond, —O—, (C₁-C₃)alkylene, —C(O)—,—SO₂—, —NR¹C(O)NR¹—, —NR¹C(O)—, —C(O)NR¹—, —(C₁-C₃-alkylene)_(p)NR¹— and—NR¹—(C₁-C₃-alkylene)_(p) where R¹ is hydrogen or alkyl and p is zero orone, provided that when Q is one of —NR¹C(O)NR¹—, —NR¹C(O)—, —C(O)NR¹—,—(C₁-C₃-alkylene)_(p)NR¹, or —NR¹—(C₁-C₃-alkylene)_(p) and p is not zeroQ is not attached to a nitrogen atom; L is selected from the groupconsisting of a covalent bond, (C₁-C₄)alkylene, substituted(C₁-C₄)alkylene, (C₂-C₄)alkenylene, and substituted (C₂-C₄)alkenylene,(C₃-C₈)cycloalkylene, and substituted (C₃-C₈)cycloalkylene; andtautomers, isomers, prodrugs and pharmaceutically acceptable saltsthereof.
 2. A compound according to claim 1, wherein said compound isrepresented by formula Ia:

wherein: W is selected from the group consisting of —O—, —S—, —S(O)—,—S(O)₂— and —NR¹—, and tautomers, isomers, prodrugs and pharmaceuticallyacceptable salts thereof.
 3. The compound according to claim 2, whereinsaid compound is represented by formula Ib:

and tautomers, isomers, prodrugs and pharmaceutically acceptable saltsthereof.
 4. The compound according to claim 3, wherein said compound isrepresented by formula II:

where each R³ is independently selected from the group consisting ofalkyl, substituted alkyl, aryl, substituted aryl, heteroaryl andsubstituted heteroaryl; n and z, and z′ are independently integers equalto zero, one or two; with the proviso that both z and z′ are not zero;and tautomers, isomers, prodrugs, and pharmaceutically acceptable saltsthereof.
 5. The compound according to claim 3, wherein said compound isrepresented by formula III:

where each R³ is independently selected from the group consisting ofalkyl, substituted alkyl, aryl, substituted aryl, heteroaryl andsubstituted heteroaryl; n and z, are independently integers equal tozero, one or two; and tautomers, isomers, prodrugs, and pharmaceuticallyacceptable salts thereof.
 6. The compound according to claim 3, whereinsaid compound is represented by formula IV:

where each R³ is independently selected from the group consisting ofalkyl, substituted alkyl, aryl, substituted aryl, heteroaryl andsubstituted heteroaryl; n and z, are independently integers equal tozero, one or two; and tautomers, isomers, prodrugs, and pharmaceuticallyacceptable salts thereof.
 7. The compound of claim 3 wherein thefragment “ring A” is selected from the group consisting of optionallysubstituted piperidine, piperazine, morpholine, piperazinone,piperazindione, azetidine, hydantoin, oxazolidine,octahydro-pyrrolo[3,4-c]pyrrole, tetrahydropyridine, hexene, pyrrolidine8. The compound of claim 7 wherein the fragment “R-T-ring A-Q” isselected from

where each b is independently 0 or 1 and each “A ring” is optionallysubstituted with from 0 to 2 substituents independently selected fromhydrogen, (C₁-C₆)alkyl, (C₁-C₆)substituted alkyl, aryl, substitutedaryl.
 9. The compound of claim 3 wherein “ring A” is a cycloalkylene orsubstituted heterocycloalkylene, which is an optionally substitutedbicyclic or spirocyclic group.
 10. The compound of claim 9 wherein“R-T-ring A-Q” is selected from

where each b is independently 0 or 1 and each “A ring” is optionallysubstituted with from 0 to 2 substituents independently selected fromhydrogen, (C₁-C₆)alkyl, (C₁-C₆)substituted alkyl, aryl, substitutedaryl.
 11. The compound according to claim 3, wherein R is aryl orsubstituted aryl.
 12. The compound according to claim 3, wherein t isselected from the group consisting of phenyl, naphthyl,3,4-dimethoxyphenyl, 4-trifluoromethoxyphenyl, 4 methylphenyl,4-trifluororomethylphenyl, 4-nitrophenyl, 4-acetylphenyl, thiophen-2-yl,biphenyl, 5-(N,N-dimethylamino)-naphthalenyl, 4-fluorophenyl, methyl,benzyl, 2-hydroxyethyl, 2-aminoethyl, and 2-phenylethyl.
 13. Thecompound of claim 3, wherein Q is a covalent bond and the ring definedby A above is piperidinyl or piperazinyl.
 14. The compound according toclaim 3, wherein X is —N═ and Y is ═CH—.
 15. The compound according toclaim 14, wherein L is alkenylene.
 16. The compound according to claim15, wherein L is a (E)-ethylenylene.
 17. The compound of claim 3 whereinT is selected from the group consisting of a bond, —SO₂—, —SO₂NH—, and—CH₂NR¹⁶—.
 18. A compound according to claim 1, which compound isselected from the group consisting of:1-(2-naphthylsulfonyl)-4-(5-hydroxyaminocarbonylthiazol-2-yl)piperazine;1-(2-naphthylsulfonyl)-4-(5-hydroxyaminocarbonylthiazol-2-yl)-1,4-diazepane;1-(2-naphthylsulfonyl)-4-(4-hydroxyaminocarbonylthiazol-2-yl)piperazine;1-(2-naphthylsulfonyl)-4-[(5-(2-hydroxyaminocarbonylethen-1(E)-yl-thiazol-2-yl)piperazine;1-(phenylsulfonyl)-4-[(5-(2-hydroxyaminocarbonylethen-1(E)-yl-thiazol-2-yl)piperazine;1-(3,4-dimethoxyphenylsulfonyl)-4-[(5-(2-hydroxyaminocarbonylethen-1(E)-yl-thiazol-2-yl)piperazine;1-(4-methoxyphenylsulfonyl)-4-[(5-(2-hydroxyaminocarbonylethen-1(E)-yl-thiazol-2-yl)piperazine;1-(4-trifluoromethoxyphenylsulfonyl)-4-[(5-(2-hydroxyaminocarbonylethen-1(E)-yl-thiazol-2-yl)piperazine;1-(4-methylphenylsulfonyl)-4-[(5-(2-hydroxyaminocarbonylethen-1(E)-yl-thiazol-2-yl)piperazine;1-(4-trifluoromethylphenylsulfonyl)-4-[(5-(2-hydroxyaminocarbonylethen-1(E)-yl-thiazol-2-yl)piperazine;1-(4-nitrophenylsulfonyl)-4-[(5-(2-hydroxyaminocarbonylethen-1(E)-yl-thiazol-2-yl)piperazine;1-(thien-2-ylsulfonyl-4-[(5-(2-hydroxyaminocarbonylethen-1(E)-yl-thiazol-2-yl)piperazine;1-(1,1′biphenylsulfonyl)-4-[(5-(2-hydroxyaminocarbonylethen-1(E)-yl-thiazol-2-yl)piperazine;1-(5-dimethylamino-naphthalene-1-sulfonyl)-4-[(5-(2-hydroxyaminocarbonylethen-1(E)-yl-thiazol-2-yl)piperazine;1-(4-fluorophenylsulfonyl)-4-[(5-(2-hydroxyaminocarbonylethen-1(E)-yl-thiazol-2-yl)piperazine;4-(2-naphthylsulfonylamino)-1-[(5-(2-hydroxyaminocarbonyl-thiazol-2-yl)-piperadine;4-(1,1′-biphenylsulfonylamino)-1-[(5-(2-hydroxyaminocarbonyl-thiazol-2-yl)-piperadine;4-(3,4-dimethoxyphenylsulfonylamino)-1-[(5-(2-hydroxyaminocarbonyl-thiazol-2-yl)-piperadine;4-(4-methylphenylsulfonylamino)-1-[(5-(2-hydroxyaminocarbonyl-thiazol-2-yl)-piperadine;2-(4-{[(1,1′-biphenylsulfonyl)amino]methyl}piperidin1-yl)-1,3-thiazole-5-carboxylic acid hydroxyamide;2-{[1-(2-naphthylsulfonyl)piperidin-4-yl]amino}-1,3-thiazole-5-carboxylicacid hydroxyamide;2-(6-{[(4-methylphenyl)sulfonyl]amino}-3-azabicyclo[3.1.0]hex-3-yl)-1,3-thiazole-5-carboxylicacid hydroxyamide;2-[3-[(4-methylphenyl)sulfonyl]tetrahydropyrimidin-1(2H)-yl]-1,3-thiazole-5-carboxylicacid hydroxylamide; 2-[4-(3,4-dimethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic acid hydroxyamide;2-[4-(4-trifluoromethoxy-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic acid hydroxyamide;2-[4-(4 toluene-4-sulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic acidhydroxyamide;2-[4-(4-trifluoromethyl-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylicacid hydroxyamide; 2-[4-(4-nitro-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic acid hydroxyamide;2-[4-(4-acetyl-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylicacid hydroxyamide;2-[4-(thiophene-2-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylicacid hydroxyamide;2-[4-(biphenyl-4-sulfonyl)-piperazin-1-yl]-thiazole-5-carboxylic acidhydroxyamide;2-[4-(5-dimethylamino-naphthalene-1-sulfonyl)-piperazin-1-yl]-thiazole-5-carboxylicacid hydroxyamide;2-[4-(4-fluoro-benzenesulfonyl)-piperazin-1-yl]-thiazole-5-carboxylicacid hydroxyamide; 2-(4-methyl-piperazin-1-yl)-thiazole-5-carboxylicacid hydroxyamide; 2-(4-Benzyl-piperazin-1-yl)-thiazole-5-carboxylicacid hydroxyamide (16b-hydroxamate);2-(4-(2-hydroxyethyl)-piperazin-1-yl)-thiazole-5-carboxylic acidhydroxyamide; 2-(4-(2-aminoethyl)-piperazin-1-yl)-thiazole-5-carboxylicacid hydroxyamide;2-(4-phenylethyl-piperazin-1-yl)-thiazole-5-carboxylic acidhydroxyamide; 2-(4-(2-oxo-2-phenylethyl %piperazin-1-yl)-1,3-thiazole-5-carboxylic acid hydroxyamide;2-(4-acetyl-piperazin-1-yl)-thiazole-5-carboxylic acid hydroxamide;2-(4-benzoyl-piperazin-1-yl)-thiazole-5-carboxylic acid hydroxamide;2-(4-phenylacetyl-piperazin-1-yl)-thiazole-5-carboxylic acidhydroxamide;2-[4-(3-{1H-indol-3-yl}propanoyl)-piperazin-1-yl]-1,3-thiazole-5-carboxylicacid hydroxyamide;N-(2-naphthylsulfonyl)-N′-{2-[5-(N-hydroxycarboxamido)]thiazolyl}-piperazine;2-[1-(1,1′-biphenyl-4-ylsulfonyl)piperidin-4-yl]-1,3-thiazole-5-carboxylicacid hydroxyamide; and pharmaceutically acceptable salts, isomers,tautomers, and prodrugs thereof
 19. A pharmaceutical compositioncomprising an effective amount of a compound according to claim 1, apharmaceutically inert carrier, and, optionally, at least one otheranti-cancer agent selected from the group consisting of platinumcoordination compounds, taxane compounds, topoisomerase I inhibitors,topoisomerase II inhibitors, anti-tumour vinca alkaloids, anti-tumournucleoside derivatives, alkylating agents, anti-tumour anthracyclinederivatives, HER2 antibodies, estrogen receptor antagonists, selectiveestrogen receptor modulators, aromatase inhibitors, retinoids, retinoicacid metabolism blocking agents (RAMBA), DNA methyl transferaseinhibitors, kinase inhibitors, farnesyltransferase inhibitors, otherHDAC inhibitors, carboplatin, oxalyplatin, paclitaxel, docetaxel,irinotecan, topotecan, etoposide, teniposide, vinblastine, vincristine,vinorelbine, 5-fluorouracil, gemcitabine, capecitabine,cyclophosphamide, chlorambucil, carmustine, lomustine, daunorubicin,doxorubicin, darubicin, mitoxantrone, trastuzuma, tamoxifen, toremifene,droloxifene, faslodex, raloxifene, exemestane, anastrozole, letrazole,vorozole, vitamin D, accutane, azacytidine, flavoperidol, imatinibmesylate, and gefitinib.
 20. A method for inhibiting a proliferativedisorder in a mammalian patient which method comprises administering tosaid patient a pharmaceutical composition according to claim 19.